Dietary supplement and related method

ABSTRACT

A composition including a unique combination of fruits, vegetables, herbs, and optionally vitamins, minerals and specialty ingredients. The composition can include a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient, is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary. The composition can be administered to subjects to correct a dietary deficiency of phytochemicals and other nutrients, improve plasma concentrations of antioxidant nutrients, and increase the activity of genetic mechanisms for DNA repair and stability.

This is a continuation-in-part application of U.S. application Ser. No. 10/915,784, filed Aug. 11, 2004, which is a continuation-in-part application of U.S. application Ser. No. 10/360,789, filed May 7, 2002 (now U.S. Pat. No. 6,989,161), which is a continuation-in-part application of U.S. application Ser. No. 09/878,377, filed Jun. 12, 2001 (now U.S. Pat. No. 6,511,675), which claims benefit of U.S. Provisional Application No. 60/210,746, filed Jun. 12, 2000, all of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to a composition and method for correcting a dietary deficiency, including an inadequacy of phytochemicals, vitamins and minerals.

Many people fail to practice healthy eating habits, such as consuming an adequate quantity and variety of food to meet U.S. Recommended Dietary Allowances. Only 22% of the subjects of a National Cancer Institute Study consumed the recommended daily number of dietary servings of fruits and vegetables—despite the fact that the recommended dietary intake of fruits and vegetables is well-known. For example. The California Daily Food Guide; Dietary Guidelines for California, California Department of Health Services (1990) recommends that each person consume at least five to nine servings of fruit and vegetables per day, including one serving of a vitamin A-rich deep green or dark orange fruit or vegetable, and at least one serving of a vitamin C-rich fruit or vegetable. Additionally, it is well reported that each person should consume at least 3 servings per week of vegetable protein in the form of legumes, nuts, or seeds. Some researchers suggest that a target of 400 grams (13 ounces) of fruits and vegetables is a sensible goal for the optimal quantity to be consumed daily. In terms of variety, it is recommended that persons should eat at least three different colors of fruits and vegetables daily.

The benefits of consuming a sufficient amount and variety of fruits and vegetables are many. For example, consuming fruits and vegetables has been shown to reduce the risk of a variety of degenerative diseases. In a prospective cohort study of 41,837 postmenopausal women, the association of fruit and vegetable consumption with lung cancer risk was investigated. The researchers found that the risk of lung cancer was approximately halved when the consumption of fruits and vegetables increased from 24 or less servings to an excess of 48 servings per week. Similarly, the risk of lung cancer was approximately halved when the consumption of green leafy vegetables, including spinach and parsley sources, increased from one or fewer servings to six or more servings per week. Steinmetz, K. et al., “Vegetables, Fruit, and Lung Cancer in the Iowa Women's Health Study,” Cancer Res. 53:536-43 (1993). Another study found that an increased intake of fresh tomatoes (a major source of lycopene) was associated with a pattern of protection for all sites of digestive tract cancer. Stahl, W. et al., “Lycopene: A Biologically Important Carotenoid for Humans?” Arc. Biochem. Biophys. 336:1-9 (1996).

In addition to fruits and vegetables, herbs also provide health benefits. For example, the herb, rosemary, contains antioxidants such as carnosol, which may play a preventive role in cholesterol oxidation. Likewise, the herb, basil is known for its antioxidant activity. Like fruits and vegetables, however, the dietary intake of beneficial herbs is unsatisfactory.

Further research has shown that the typical U.S. diet is lacking in phytochemicals. Phytochemicals generally refer to plant-derived compounds which, when taken daily in combination with vitamins and minerals, provide improved cardiovascular and bone health, an improved antioxidant profile, decreased free radical damage, and overall enhancement of the body's natural defense system.

The typical diet, especially the U.S. diet, includes an inadequate amount and variety of fruits, vegetables and herbs, as well as the phytochemicals and associated antioxidants present in these materials. A typical diet is similarly deficient in necessary vitamins and minerals associated with fruits and vegetables. Although conventional multivitamins can supplement western diets with needed vitamins and minerals, many of these multivitamins fail to provide phytochemicals that target free radicals in the body and thereby improve the antioxidant profile of the supplement.

SUMMARY OF THE INVENTION

The present invention provides a composition including a unique combination of fruit vegetable, and herb dehydrates, concentrates, or extracts; and optionally vitamins, minerals and specialty ingredients to correct a dietary deficiency of those materials.

The composition of the present invention provides substantial health benefits. For example, in one embodiment, it can support the health of people who consume a nutritionally deficient diet; improve antioxidant and nutrient status; replenish serum nutrient and phytochemical levels as a result of inadequate diets to levels associated with decreased risk of certain degenerative disease states; minimize free radical damage that occurs as a result of normal aging processes and exposure to environmental stresses; and/or improve the status of specific biomarkers indicative of optimal health, namely homocysteine, lipid byproducts, mineral status and glutathione peroxidase.

In a more specific embodiment, the composition of the present invention can provide p-carotene, a-lipoic acid, selenium, and vitamins C and E, which improve the antioxidant profile of a person. Increased levels of folic acid and vitamins E target and improve cardiovascular health. Calcium, magnesium, and vitamin D targets and improves bone health. B vitamins improve energy metabolism. The compositions according to the invention can provide 100% of the U.S. Recommended Daily Intake of all vitamins and most minerals. The composition also can provide a variety of phytochemicals to produce a diverse antioxidant profile.

In an even more specific embodiment, the composition can include a combination of fruit, vegetable and herbal ingredients, wherein the fruit ingredients are selected from acerola, apple, blueberry, citrus bioflavonoids, cranberry, grape skin, plum, and pomegranate; wherein the vegetable ingredients are selected from asparagus, alfalfa, brassica, kale, lutein, lycopene, and watercress; and wherein the herbal ingredients are selected from basil, oregano, parsley, sage and rosemary. These ingredients can be concentrated, for example they may be extracted from raw ingredients. Optionally, the fruit ingredients, vegetable ingredients and herbal ingredients can be present in the composition in a ratio of about 3.5:1:1 by weight. Specialty ingredients, such as alpha lipoic acid and inositol can be added to the composition.

In yet another embodiment, the composition can include at least one fruit ingredient selected from the group consisting of citrus bioflavonoids and pomegranate, and optionally at least one of acerola, apple, blueberry, cranberry, grape skin, plum and raspberry; at least one vegetable ingredient selected from the group consisting of asparagus, lutein, lycopene, and watercress, and optionally at least one of alfalfa, brassica, and kale; and at least one herbal ingredient selected from the group consisting of basil, oregano and rosemary, and optionally at least one of parsley and sage.

In another embodiment, a method is provided for enhancing the immune system, as well as treating and/or reducing die risk of DMA damage of the human body comprising administering an effective amount of a composition including at least one fruit ingredient selected from the group consisting of citrus bioflavonoids and pomegranate, and optionally at least one of acerola, apple, blueberry, cranberry, grape skin, and plum; at least one vegetable ingredient selected from the group consisting of asparagus, lutein, lycopene, and watercress, and optionally at least one of alfalfa, brassica, and kale; and at least one herbal ingredient selected from the group consisting of basil, oregano and rosemary, and optionally at least one of parsley and sage.

These and other objects, advantages and features of the invention will be more readily understood and appreciated by reference to the detailed description of the invention and the drawings. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting the effect the composition has on Vitamin C levels.

FIG. 2 is a graph depicting the effect the composition has on beta carotene levels.

FIG. 3 is a graph depicting the effect the composition has on Vitamin B₆ levels.

FIG. 4 is a graph depicting the effect the composition has on Vitamin B₁₂ levels.

FIG. 5 is a graph depicting the effect the composition has on Folate levels.

FIG. 6 is a graph depicting the effect the composition has on homocysteine levels.

FIG. 7 is a graph depicting the numbers of genes related to DNA or chromatin maintenance or repair that were modulated by consumption of the composition.

FIGS. 8A and 8B which are a diagram (FIG. 8A) and a graph (FIG. 8B) depicting decreased oxidative stress with treatment using the composition of the present invention as indicated by decreased concentration of 2-hydroxybutarate.

FIGS. 9A and 9B are a diagram (FIG. 9A) and a graph (FIG. 9B) depicting decreased oxidative stress with treatment using the composition of the present invention as indicated by decreased concentration of 5-oxoproline.

FIG. 10 is a graph depicting the change in plasma beta-carotene concentration after treatment.

FIG. 11 is a graph depicting the change in plasma folate concentration after treatment.

FIG. 12 is a graph depicting the change in plasma vitamin B6 concentration after treatment.

FIG. 13 is a graph depicting the change in plasma vitamin B12 concentration after treatment.

FIG. 14 is a graph depicting the change in plasma homocysteine concentration after treatment.

FIG. 15 is a graph depicting the change in DNA damage after treatment.

FIG. 16 is a graph depicting the change in baseline expression activity of genes associated with DNA maintenance genes after treatment.

DETAILED DESCRIPTION OF THE INVENTION I. Overview

In general, the invention relates to a composition comprising fruits, vegetables and herbs. In one embodiment, the composition can include a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary. The composition can also be combined with a known therapy that can impact chromatin stability thereby limiting the detrimental effects of such therapy.

The following fruit ingredients also can be present in the composition: acerola, apple, blueberry, cranberry, grape skin, and plum. Further, the following vegetable ingredients also can be present in the composition: alfalfa, brassica, and kale. Finally, the following herbal ingredients also can be present in the composition: sage and parsley.

The composition has a synergistic effect in the treatments discussed herein. Thus, the components of the composition together are more effective that individually. Additionally, the composition modulates, and more specifically as discussed herein up-regulates, genes associated with chromatin stability, examples of which are discussed in the figures and examples.

Example of genes involved in telomere maintenance include, but are not limited to, Ku, Cdc 13 protein, the catalytic subunit EST2, and three other genes, EST1, EST3, EST4/CDC13, MRE11, RAD50, XRS2 (yeast)/NBS1, p53, hTERT, ATM, TRF2, the TERF family of genes.

The composition of the present invention can either treat or reduce the occurrences/risks of chromatin damage, and thus support genome stability, by increasing the expression of genes involved in identifying and correcting damage to DNA as well as associated protein structures (i.e., chromatin). The reduction in the occurrence/risk of chromatin damage includes any statistically significant reduction that correlates to a biological response or outcome. These genes control activities including, but not limited to, repair of base pair mismatches, repair of double strand breaks, or other maintenance, repair or supervisory roles. Most damage is caused by oxidation, nutrient deficiency, radiation or toxins. There are four main types of damage to DNA due to endogenous cellular processes or exogenous insult such as ultraviolet radiation: oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species, alkylation of bases (usually methylation), such as formation of 7-methylguanine, 1-methyladenine, O6 methylguanine hydrolysis of bases, such as deamination, depurination and depyrimidination, mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted. There are four major DNA-repair pathways in human cells: mismatch repair, nucleotide-excision repair (NER), base-excision repair (BER), and double-strand-break (DSB) repair. The NER pathway mainly removes bulky DNA adducts. The BER pathway is responsible for removal of oxidized DNA bases that may arise endogenously or from exogenous agents. The DSB pathway is responsible for repairing double-strand breaks caused by a variety of exposures, including ionizing radiation, free radicals, and telomere dysfunction. Examples of such genes include, but are not limited to ERCC, RAD2, RAD6, RAD7, RAD18, RAD23, RAD51, RAD54, CDC7, CDC8, CDC9, MAG1, PHR1, DIN1, DDR48, RNR1, RNR2, RNR3, UB14, repB, repD and APE. These genes are impacted by the composition of the present invention can modulate any of the types of damage disclosed above.

The composition can thus be used to treat diseases associated with DNA repair problems including, but not limited to, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy, Werner's syndrome, Bloom's syndrome and ataxia telangiectasia. All of which are associated with improper repair of DNA.

The composition can also be used to affect/modulate the function of mitochondria function-specific genes, examples of such genes are provided in Table 8 below. These genes generally fall into four categories. First, genes for mitochondrial transcription/translation, examples of which include, but are not limited to, MTRF1L, which is involved in mitochondrial translational machinery, GFM2, which is a protein involved in protein elongation, MRPL3, which is a mitochondrial ribosomal protein, TOMM20, which is a central component of the receptor complex responsible for the recognition and translocation of cytosolically synthesized mitochondrial preproteins and together with TOM22 functions as the transit peptide receptor at the surface of the mitochondrion outer membrane and facilitates the movement of preproteins into the TOM40 translocation pore. COX15, which is predominantly found in tissues characterized by high rates of oxidative phosphorylation (OxPhos) involved in heme biosynthesis, POLG2, mtDNA that is replicated accurately by DNA polymerase gamma, and MRPS10, which is part of mitochondrial 28S Ribosomal protein. Second, genes for mitochondrial structure examples of such genes include, but are not limited to, DNMIL, which is critical for maintenance of mitochondrial morphology, OPA1, which is a major organizer of the mitochondria); inner membrane and is required for the maintenance of cristae integrity, MFN1, which is an essential transmembrane GTPase, which mediates mitochondrial fusion (MFN1 acts independently of the cytoskeleton.), BNIP3, which provides regulation of mitochondrial permeability, COX18, which is required for the insertion of integral membrane proteins into the mitochondrial inner membrane and is essential for the activity and assembly of cytochrome c oxidase and plays a central role in the translocation and export of the C-terminal part of the COX2 protein into the mitochondrial intermembrane space, and DNM1L, which functions in mitochondrial and peroxisomal division probably by regulating membrane fission and enzyme hydrolyzing GTP that oligomerizes to form ring-like structures and is able to remodel membranes. Third, miscellaneous mitochondrial proteins examples of such genes include, but are not limited to, WWOX, a tumor suppressor gene, PPIF, for protein folding, CoQ9, 10GB, which is involved in the final steps in the synthesis of CoQ, SLC25A37, which is a mitochondrial iron transporter that specifically mediates iron uptake in developing erythroid cells, thereby playing an essential role in heme biosynthesis, ABCB7, which is involved in the transport of heme from the mitochondria to the cytosol, and SLC25A36, which is a transporter for mitochondria. Fourth, genes for mitochondrial enzymes examples of such genes include, but are not limited to, SDHD, which is part of the respiratory chain, ATPAF1 enzymes which are critical for generation of ATP, NARS2, IARS2, EARS2, LARS2, HARS2, which are enzymes involved in the production of amino acid, ASN, ILE and GLN, LEU and HIS respectively, HIBADH, which is an enzyme providing succinyl coA for TCA cycle, ACADSB, which is an enzyme catalyzing one of the steps in fatty acid beta oxidation, MIB1, which is a E3 ligase necessary for protein ubiquitnation (deletion lethal), BCKDHB and ACAD8, for the generation of succiny Co A for TCA, AFG3L2, which is a AAA protease protecting against oxiative stress, PEO1, which is a DNA helicase, critical for lifetime maintenance of mtDNA integrity and to maintain mtDNA copy number, HK2 (Hexokinase 2), and HADHB, which is involved in fatty acid beta-oxidation.

The composition can also be combined with a known therapy to create a combinatorial therapy. This can primarily be used in instances where the known therapy has known detrimental side effects that impact DNA stability, such as chemotherapeutics and radiotherapeutics. Other compounds can also be used that negatively impact DNA repair and stability.

The invention also relates to a method for correcting a diet-induced deficiency of fruits, vegetables and herbs, and the nutrients present in such materials. The composition of the present invention additionally can contain phytochemicals, vitamins, and minerals known to improve the body's natural defenses against oxidants, free radicals, and diseases.

II. Composition and Method of Manufacture

The composition can include a combination of fruit, vegetable, herbal and other ingredients that provide significant health benefits. The following tables illustrate representative daily amounts of suitable fruits, vegetables, herbs, vitamins, and minerals which can be included in the composition. The dosages and methods of administration can be varied as desired from application to application. For example, Dosage A represents a range of dosages of the respective ingredients that is suitable for purposes of the present, invention. Dosage B represents a dosage of a particular embodiment. The unit “mg” in Tables 1-5 means that that the amount recited is given in the number of, e.g., milligrams, provided in a two-tablets per day dosage, unless otherwise noted, e.g., “JU” is recited. Thus, to determine the amount of a specific ingredient per single tablet, the amount recited in the respective tables must be halved.

TABLE 1 Fruit Ingredient Dosage A, mg/day Dosage B, mg/day Acerola Powder 50-500  300 Apple extract 25-1000 50 Citrus Bioflavanoids 25-1000 100 Grape skin extract 25-1000 50 Plum extract 25-1000 50 Cranberry extract 25-1000 50 Pomagranate 5-500 25 Blueberry extract 25-1000 50

The citrus bioflavonoids are commercially available from Access Business Group International LLC of Ada, Mich. This ingredient can be in a concentrate form, and can include, but are not limited to, naringen, hesperidin, narirutin, diosmin, rutin, tangeretin, diosmetin, neohesperidin, nobiletin, and quercetin.

TABLE 2 Vegetable Ingredient Dosage A, mg/day Dosage B, mg/day Asparagus 25-1000 50 Alfalfa 25-1000 70 Brassica 25-1000 50 Kale 20-1000 75 Lycopene 0.1-100   2 Lutein esters 0.1-100   2 NUTRILITE Watercress 5-500 28

NUTRILITE watercress is available from Access Business Group International LLC. The Brassica and/or kale can be in dehydrated, powdered form. As used herein the Brassica ingredient may include any material derived from plants in the Brassicae family, for example, broccoli. The lutein esters used in the composition can be of the type sold under the name Xangold 10% beadlets, which is available from Cognis Nutrition & Health of Cincinnati, Ohio. The lycopene used in the composition can be of the type sold under the name Lycobeads 5%, which is available from H. Reisman Corp. of Orange, N.J.

TABLE 3 Vegetable Ingredient Dosage A, mg/day Dosage B, mg/day Basil extract 25-1000 50 Rosemary extract 25-1000 50 Sage 5-500 25 Oregano extract 25-1000 50 NUTRILITE Parsley 5-500 25

NUTRILITE parsley is available from Access Business Group International LLC. The composition can also include ingredients in addition to the fruit, vegetable and herbal ingredients noted above. For example, suitable vitamins for use in the compositions and methods of the present invention can include, vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacin/niacinamide, pantothenic acid, folic acid, biotin, choline, vitamin C, vitamin D, and vitamin E. Table 4 below includes a suitable vitamin profile.

TABLE 4 Vitamin Profile Dosage B, Ingredient Dosage A, mg/day mg/day Vitamin C from Acerola 20-100 60 Powder Ascorbic Acid (C) 100-700  440 Vitamin A from Beta Carotene 1000-10,000 IU 7500 IU Biotin 0.01-4    0.300 Pantothenic Acid from Cal  5-300 50 Pan Gran Choline 10-400 50 Folic Acid 0.01-10   0.8 Inositol  5-100 25 Vitamin E 10-5000 IU 150 IU Mixed Tocopherols  5-300 50 Niacin/Niacinamide  5-300 40 Pyridoxine (B6) 10-100 15 Riboflavin (B2)  1-100 12.75 Thiamine (B1)  1-100 11.25 Vitamin A from Acetate 100-10,000 IU 2500 IU Vitamin B12 0.01-50   0.045 Vitamin D3 10-2000 IU 400 IU Yeast, Standardized@  5-350 60 (source of 100% RDA Bs)

In addition to the vitamins listed above, minerals for use in the compositions and methods of the present invention include, for example, boron, calcium, chromium, copper, iodine, magnesium, manganese, molybdenum, potassium, selenium, vanadium, and zinc. Other vitamins and minerals may also be used. Table 5 below includes a mineral profile suitable for the composition of the present invention.

TABLE 5 Mineral Profile Ingredient Dosage A, mg/day Dosage B, mg/day Calcium 100-2000 750 Chromium 0.01-5    0.120 Copper 0.01-5    2 Iodine 0.001-5    0.15 Magnesium  10-1000 300 Manganese 1-20 5 Molybdenum 0.001-75    0.075 Potassium  5-300 80 Selenium 0.001-5    0.100 Zinc 1-50 15

With the ingredients of Tables 1-3, and optionally the ingredients of Tables 4-5, the composition of the present invention can provide a significant portion of, and in many cases exceed, the recommended daily requirement for a variety of vitamins and minerals. Tables 6 and 7 below illustrate the potency of the composition, when taken in the above daily amounts, in terms of percentages of the daily requirements for the listed vitamins and minerals.

TABLE 6 Vitamin Amount/Day % Daily Value Vitamin A (75% as β- 10,000 200% Carotene), IU Vitamin C, mg 500 833% Vitamin D, IU 400 100% Vitamin E, IU 150 500% Niacin/Niacinamide, mg 40 200% Vitamin B₆, mg 15 750% Vitamin B₁₂, mcg 45 750% Folic Acid, mcg 800 200% Biotin, mcg 300 100% Pantothenic Acid, mg 50 500%

TABLE 7 Minerals Amount/Day % Daily Value Calcium, mg 750  75% Magnesium, mg 300  75% Iodine, mcg 150 100% Potassium, mg 80  2% Copper, mg 2 100% Zinc, mg 15 100% Manganese, mg 5 100% Chromium, mcg 120 100% Selenium, mcg 100 143% Molybdenum, mcg 75 100%

Additional specialty ingredients which can be used in the composition include, for example, methyl sulfonyl methane (MSM), α-lipoic acid (10 mg/day), catechins, polyphenols, flavanoids, lycopene, lutein, yeast, inositol, and para-aminobenzoic acid (PABA).

The composition of the present invention can be formulated using any pharmaceutically acceptable form of respective fruit concentrates, vegetable concentrates, herb concentrates, phytochemicals, vitamins, minerals, and other nutrients, including their salts. The compositions can be formulated into tablets, powders, gels, or liquids (a tablet, for the purposes of the present invention and as used throughout the application disclosure, refers to any form of a solid oral dosage, including but not limited to tablets, caplets, capsules, powders, etc.). The compositions can be formulated as powders, for example, for mixing with consumable liquids such as milk, juice, water, or consumable gels or syrups for mixing into other liquids or foods. The compositions can also be formulated with other foods or liquids to provide pre-measured compositional foods, for example, single-serving bars. Flavorings, binders, protein, complex carbohydrates, and the like can be added as needed.

According to one aspect of the invention, the composition is administered as three separate tablets, all three of which are administered twice a day; however, the composition may be administered in other forms and unit dosages as desired.

The composition of the present invention will be illustrated by, but is not intended to be limited to, the following examples.

EXAMPLE 1

Three tablets may be prepared to provide a) fruit, vegetable and herbal ingredients, b) vitamins and c) minerals. The first tablet includes the fruit, vegetable and herbal ingredients of Tables 1-3. The amount of each ingredient in this first tablet is half of the amount listed in the Dosage B of the Tables, as the table-listed amount is the amount present in two such tablets. The first tablet may also include carriers and other tableting aids such as silicon dioxide, magnesium oxide, calcium carbonate, croscarmellose sodium, microcrystalline cellulose and magnesium stearate in amounts that may be varied for purposes well known to those of skill in the art.

The second tablet includes vitamins of Table 4. The amount of each ingredient in this second tablet is half of the amount listed in the Table, as the table-listed amount is the amount present in two such tablets. The second tablet may also include carriers and other tableting aids such as microcrystalline cellulose, calcium carbonate, croscarmellose sodium, magnesium stearate, and silicon dioxide.

The third tablet includes minerals of Table 5. The amount of each ingredient in this third tablet is half of the amount listed in the Table, as the table-listed amount is the amount present in two such tablets. The third tablet may also include carriers and other tableting aids such as microcrystalline cellulose, calcium carbonate, croscarmellose sodium, magnesium stearate, and silicon dioxide.

The three tablets, when administered twice a day, complete the gap in phytochemicals that is present in the typical diet.

EXAMPLE 2

The following examples relate to methods of preparing the above three tablets. The ingredients are the same as those referred to above in Tables 1-5. For purposes of the following examples, however, tablets including the fruit, vegetable and herbal ingredients from Tables 1-3 are referred to as “Tablet 1”; tablets including the vitamin ingredients from Table 4 are referred to as “Tablet 2”; and tablets including the mineral ingredients from Table 5 are referred to as “Tablet 3.” It is noted that other methods for preparing the tablets and other suitable delivery vehicles can be used as desired.

Tablet 1

Mixed tocopherols, D-alpha-tocopherol (succinate), and silicon dioxide (NF fine powder) are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes Magnesium oxide (D.C. heavy), Acerola concentrate, citrus bioflavonoids complex, plum extract, apple extract, rosemary extract, basil extract, grape skin extract, cranberry extract, kale powder, asparagus extract, blueberry extract, parsley dehydrate, oregano extract, sage extract, pomegranate extract, and inositol are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes.

Lycopene (5%), lutein ester (beadlets), mixed tocopherols, calcium carbonate (granular), croscarmellose sodium and microcrystalline cellulose (silicified) are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The mixture is blended for ten minutes. Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for an additional five minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.

Tablet 2

Acerola concentrate, microcrystalline cellulose (silicified) and alpha lipoic acid are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot P.K. blender. The ingredients are blended for ten minutes. Next, the following ingredients are passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender: thiamine mononitrate (97%), riboflavin, niacinamide, biotin trituration (1%), vitamin B12 (1.1%), calcium pantothenate granular, folic acid, pyridoxine HCl (95%), and choline bitartrate. The ingredients are blended for ten minutes. Next, the following items are passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender; beta carotene (beadlets), vitamin D3 (beadlets), yeast (standardized) and vitamin A (acetate). The mixture is blended for an additional ten minutes.

Next, the following ingredients are passed through a SWECO separator equipped with a 20 mesh screen directly into the 1.00 cubic foot PK blender: ascorbic acid (97%), calcium carbonate (granular), croscarmellose sodium, d-alpha-tocopherol succinate, silicon dioxide (NF fine powder). The mixture is blended for an additional ten minutes.

Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender. The mixture is blended for an additional five minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.

Tablet 3

Zinc amino acid chelate, mixed tocopherols and silicon dioxide (NF fine powder) are passed through a SWECO separator equipped with a 20 mesh screen into a 100 cubic foot PK blender. The ingredients are blended for ten minutes. Co-processed alfalfa concentrate/microcrystalline cellulose/calcium carbonate, selenium yeast, microcrystalline cellulose, copper amino acid chelate, manganese amino acid chelate, potassium iodide trituration, chromium amino acid chelate, molybdenum amino acid chelate, brassica dehydrate, watercress dehydrate and croscarmellose sodium are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for ten minutes.

Potassium chloride, magnesium oxide (D.C. heavy) and calcium carbonate (granulation) are passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for ten minutes. Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into a 100 cubic foot PK blender. The ingredients are blended for an additional ten minutes. Next, magnesium stearate (Kosher) is passed through a SWECO separator equipped with a 20 mesh screen directly into the 100 cubic foot PK blender. The mixture is blended for an additional live minutes. The resulting mixture is discharged into totes or supersacks, and compressed into tablets.

EXAMPLE 3

The clinical study was an independent Review Board-approved, double-blind, placebo-controlled, parallel-groups study.

Subjects

Subjects were 1.20 healthy adult Japanese-Americans in California and Hawaii Subjects were ethnically Japanese (both parents and four grandparents ethnically Japanese) and ate a mostly Japanese diet

Treatment

Subjects took either composition or placebo as directed (12 tablets a day) for 8 weeks. The composition is the same formula as is currently marketed in Japan under the Alticor name of Triple X™. All products were coated and provided in coded foil packs to preserve double-blindedness.

There were four main categories of outcome measures; (1) plasma concentrations of a representative water-soluble antioxidant nutrient [vitamin c], and a representative fat-soluble antioxidant nutrient [beta carotene], (2) plasma concentrations of the “anti-homocysteine triad” vitamin B6, vitamin B12, and folate, as well as plasma concentrations of homocysteine, (3) nutrigenomic mechanisms of genomic stability, and (4) plasma metabolomic profile changes.

Analyses for plasma nutrient and homocysteine concentrations were based on blood samples obtained from 120 subjects (60 treated with Triple X, and 60 treated with Placebo), at baseline, Week 4, and Week 8.

Nutrigenomic analyses were based on blood samples obtained from 14 subjects (7 treated with Triple X, and 7 treated with Placebo) at baseline and Week 2.

Statistics

Plasma nutrient and homocysteine change score results were assessed with independent-groups t-test for between-groups comparisons. A P value smaller than 0.05 was considered significant.

Nutrigenomic data were first analyzed with paired t-tests within the composition-treated group only to identify which from among 44,000 genes measured showed a significant change in expression level following treatment. A P value smaller than 0.05 was considered significant. A Q value (false discovery rate) of 0.4 was used to control for false positive findings. This analysis identified about 2,000 genes, which were then examined for biologically relevant patterns of change.

Results from the clinical study were as follows. Compared to subjects taking Placebo, subjects taking composition showed increased levels of folate, vitamin B6, vitamin B12, and vitamin C, as well as decreased levels of homocysteine, all within 4 weeks of treatment, with results maintained at 8 weeks. Metabolomic analyses indicate decreased oxidative stress. Nutrigenomic analyses indicate increased genomic integrity and tumor suppressor mechanisms, homocysteine metabolism, resistance to oxidative stress and lipid peroxidation.

Clinical interpretation of nutrigenomic data revealed the unexpected finding that about 150 genes [Do you have a listing of the genes?], each known to function to support genomic stability (via chromatin maintenance, damage detection, and repair), were significantly increased in the Triple X group compared to the placebo group. Subsequent analysis of these genes in the Placebo-treated group showed no change following Placebo treatment. Compared to baseline, consumption of the composition of the present invention led to statistically significant increases in the expression of genes related to DNA maintenance, replication, or repair (FIG. 7).

Clinical interpretation of metabolomic data revealed the unexpected findings that consumption of Triple X led to significant decrease increases in 2-hydroxy bury rate, a metabolite related to oxidative stress (FIG. 9), as well as a trend towards a decrease in 5-oxoproline, also a metabolite related to oxidative stress (FIG. 10). This shows that the consumption of the composition can lead to increased plasma concentration of antioxidant nutrients, increased expression of chromatin maintenance and repair genes, decreased homocysteine, and decreased metabolomic indicators of oxidative stress.

EXAMPLE 4

Clinical testing was conducted to confirm the efficacy of the composition of the present invention. It was expected that consumption of the composition would: correct dietary deficiencies of phytochemicals; improve the amount of antioxidants in the body; decrease free radical damage; increase plasma vitamin, mineral and phytochemical concentrations; and improve plasma and systemic antioxidant capacity, among other things.

Inclusion criteria for this study were healthy men and women, from 18 to 80 years of age, who consume fewer than 12 items found on the Recommended Foods Checklist per week. These subjects are selected after administration of a food frequency questionnaire and application of the Recommended Foods Score (RFS). The RFS consists of 23 foods, 14 of which are fruits and vegetables, that when consumed on a weekly basis have been associated with reduced mortality. This was demonstrated in a cohort study of 42,254 women. Those with a mean RFS of 16.0 (highest quartile) had an all-cause mortality relative risk of 0.69 compared to those with a mean RFS of 6.4 (lowest quartile) who have an all-cause mortality relative risk. It was noted that those in the highest quartile consumed significantly more calories (131%), fiber (200%), Vitamin C (230%), folate (181%), and pro-Vitamin A carotenoids (253%) compared to those in the lowest quartile.

The clinical study encompassed a double-blind (i.e. to subjects and investigators) study of 120 subjects over a six-week period. During the six-week trial, subjects were told to consume three tablets, either the composition, or a placebo, twice a day, such as morning and evening. The subjects were tested by taking blood and urine samples and performing the following assays: total polyphenols, plasma ORAC (Oxygen Radical Absorption Capacity), CP450 enzyme induction, cytokinesis block micronucleus assay, comet assay, bioenergetics assay, urinary bile acids, B6, B12, folate, Vitamin C, homocysteine, alpha and gama tocopherols, beta-carotene, C-reactive protein and urinary 8-epi prostaglandins F2α, which were tested at baseline, two weeks, four weeks and six weeks into the study. Improvement, and thus, efficacy of the composition, was measured based on: plasma concentrations of vitamins, minerals and phytochemicals; plasma and systemic antioxidant capacity; detoxification capacity; cellular energy dynamics; genomic stability; other risk factors and subjective effects.

It was expected that the results of the study would show that following six weeks of composition consumption, subjects would have significantly increased plasma levels of alpha tocopherols, B12, B6, folate, Vitamin C, and other antioxidants, which indicates an improvement in the amount of antioxidants in the body and which is associated with a correction of dietary deficiencies in vitamins, nutrients and phytochemicals, and/or a decrease in free radical damage, as well as increased genomic stability (i.e., decreased DNA damage) among other things.

Results from the clinical study were as follows. Compared to subjects taking Placebo, subjects taking the composition showed increased plasma concentrations of Beta Carotene, Alpha-Tocopherol, Folate, and Vitamins B6 and B12. Subjects taking composition also showed significantly reduced homocysteine, as well as decreased DNA damage as indicated by the cytokinesis micronucleus block assay. This shows that the consumption of the composition can increase plasma concentrations of antioxidant nutrients, decrease homocysteine, and decrease DNA damage.

The above descriptions are those of the preferred embodiments of the invention. Various alterations and changes can be made without departing from the spirit and broader aspects of the invention as defined in the appended claims, which are to be interpreted in accordance with the principles of patent law including the doctrine of equivalents. Any references to claim elements in the singular, for example, using the articles “a,” “an,” “the,” or “said,” is not to be construed as limiting the element to the singular.

TABLE 8 ADH5 \alcohol Removal of S-nitrosoglutathione and Anti- dehydrogenase thus controls its levels as well as levels Nitrosative 5 (class III), of nitrosylated proteins. Protects against stress activity chi nitrosative stress. Low amounts of this gene polypeptide\“” enzyme or absence can increase whole cell nitrosylation and tissue damage and susceptibility to bacteria. TXNL1 thioredoxin- TXNL1 acts as an effector of oxidants or Anti-oxidant like 1 a redox sensor activity gene TXNRD3 thioredoxin Thioredoxin reductases (EC 1.6.4.5), Anti-oxidant reductase 3 such as TXNRD3, are selenocysteine activity gene (sec)-containing flavoenzymes that maintain thioredoxins, small proteins that catalyze redox reactions, in the reduced state using the reducing power of NADPH, sec residue of TXNRD1 serves as a sensor of reactive oxygen species. UHRF2 \ubiquitin-like, Absence of this gene makes cells more Anti-oxidant containing sensitive to X rays, UV light and activity gene PHD and hydroxyurea RING finger domains, 2\“” VPS8 vacuolar VPS3, VPS8 and PEP7 genes to rescue Anti-oxidant protein sorting lethal effects of oxidative damage activity gene 8 homolog (S. cerevisiae) resulted from the overexpression of these genes. PAFAH2 \platelet- Membrane phospholipids are Anti-oxidant Detoxification activating susceptible to oxidation, which is activity gene activity factor involved in various pathological gene acetylhydrolase processes such as inflammation, 2, 40 kDa\“” atherogenesis, neurodegeneration, and aging. One enzyme that may help to remove oxidized phospholipids from cells is intracellular type II platelet- activating factor acetylhydrolase (PAF- AH (II)), which hydrolyzes oxidatively fragmented fatty acyl chains attached to phospholipids. Overexpression of PAF- AH (II) in cells or tissues was previously shown to suppress oxidative stress- induced cell death. ME2 \malic enzyme The primary role of malic enzyme, Anti-oxidant 2, NAD(+)- however, may be to generate reduced activity gene dependent, NADP+ for biosynthesis rather than to mitochondrial\ form an intermediate of carbohydrate “” catabolism. NADPH provides the reducing equivalents for biosynthetic reactions and for oxidation-reduction involved in protection against the toxicity of ROS PON2 paraoxonase 2 The encoded protein is ubiquitously Anti-oxidant expressed in human tissues, membrane- activity gene bound, and may act as a cellular antioxidant, protecting cells from oxidative stress. Hydrolytic activity against acylhomoserine lactones, important bacterial quorum-sensing mediators, suggests the encoded protein may also play a role in defense responses to pathogenic bacteria. IVNS1ABP influenza virus Protects cells from cell death induced by Anti-viral NS1A binding actin destabilization; Protects neurons protein from dendritic spines and actin filaments damage induced by the actin- destabilizing cytochalasin B when overexpressed. May be a component of the cellular splicing machinery with a role in pre-mRNA splicing; may mediate the inhibition of splicing by NS/influenza virus NS1A protein. Highly present in neutrophil ILF3 \interleukin Nuclear factor of activated T-cells Anti-viral enhancer (NFAT) is a transcription factor required activity gene binding factor for T-cell expression of interleukin 2. 3, 90 kDa\“” NFAT binds to a sequence in the IL2 enhancer known as the antigen receptor response element 2. In addition, NFAT can bind RNA and is an essential component for encapsidation and protein priming of hepatitis B viral polymerase. NFAT is a heterodimer of 45 kDa and 90 kDa proteins, the larger of which is the product of this gene. The encoded protein, which is primarily localized to ribosomes, probably regulates transcription at the level of mRNA elongation, required for IL2 mRNA stabilization. Anti-viral activity SRPK2 SFRS protein SRPK1 and SRPK2 in HBV replication Anti-viral kinase 2 and found that both of them could activity gene suppress HBV replication by reducing the packaging efficiency of the pgRNA without affecting the formation of the viral core particles. PTX3 \pentraxin- anti-viral activity Anti-viral related gene, activity gene rapidly induced by IL- 1 beta\“” RIPK2 receptor- Anti-viral response Anti-viral interacting activity gene serine- threonine kinase 2 SMARCE1 \SWI/SNF Suppression of hepatitis B virus (HBV) Anti-viral related, matrix replication, a causative agent for chronic activity gene associated, hepatitis, is an effective approach to actin controlling disease progression. Host dependent factors have a significant effect on viral regulator of replication efficiency and need to be chromatin, better characterized.. Cellular subfamily e, transcription modulator SMARCE1 binds member 1\“” to HBV core promoter containing naturally occurring deletions and represses viral replication. Transcriptional coactivator cooperating with nuclear hormone receptors to potentiate transcriptional activation, he SWI/SNF chromatin remodeling complexes are evolutionarily conserved multimeric enzymatic machines that alter the nucleosomal structure using energy derived from ATP hydrolysis (34). Ample experimental evidence suggests that the SWI/SNF complexes play important roles in fundamental cellular processes such as transcription, replication, and the repair of chromatin TLR7 toll-like TLR7-specific agonists activate Anti-viral receptor 7 plasmacytoid DCs (pDCs) and B cells activity gene and induce mainly IFN-a and IFN- regulated cytokines, the natural ligands of TLR7 and TLR8 were identified as single-stranded RNA (ssRNA), single stranded (ss)RNA viruses [either vesicular stomatitis virus (VSV; a rhabdovirus) or influenza virus (an orthomyxovirus)] stimulate type I IFN responses through TLR7. ZNF175 zinc finger OTK18 was copiously expressed in Anti-viral protein 175 macrophages following HIV type I activity gene infection and diminished progeny virion production. A mechanism for this antiretroviral activity was by suppression of HIV type 1 Tat-induced viral long terminal repeat promoter activity. BNIP2 BCL2/adenovirus Adenovirus E1B 19-kD protein protects Anti-viral E1B against cell death induced by viral activity gene 19 kDa infection and certain external stimuli. interacting protein 2 CDKN1A \cyclin- is an endogenous cellular component in Anti-viral dependent stem cells that provides a molecular activity gene kinase barrier to HIV-1 infection., anti-viral inhibitor 1A (p21, Cip1)\“” CREBZF CREB/ATF The neuronal host cell factor-binding Anti-viral bZIP protein Zhangfei inhibits herpes simplex activity gene transcription virus replication. factor ELF1 E74-like factor ELF-1 belongs to a subset of Ets factors Blood vessel 1 (ets domain that regulate vascular-specific gene development transcription expression during blood vessel gene factor) development. NUS1 nuclear Acts as a specific receptor for the N- Blood vessel undecaprenyl terminus of Nogo-B, a neural and development pyrophosphate cardiovascular regulator. Able to gene synthase 1 regulate vascular remodeling and homolog (S. cerevisiae) angiogenesis. Its similarity with UPP synthetase proteins suggests that it may act as a scaffold for the binding of isoprenyl lipids and/or prenylated proteins. Nogo-B receptor localizes with the ligand Nogo-B during VEGF and wound healing angiogenesis in vivo, mediates chemotaxis in a heterologous expression system and chemotaxis, and 3D tube formation in native endothelial cells. Thus, identification of this receptor may lead to the discovery of agonists or antagonists of this pathway to regulate vascular remodeling and angiogenesis. CLIC4 chloride CLIC4 is involved in formation of the Blood vessel intracellular blood vessel lumen. Blood vessel development channel 4 formation. Chloride channel or a gene regulator or accessory subunit of other proteins that could provide the pore- forming function. SGPP1 sphingosine- Sphingosine-1-phosphate (S1P) is a highly Blood vessel 1-phosphate bioactive lipid that exerts numerous biological development phosphatase 1 effects both intracellularly as a second messenger gene and extracellularly by binding to its G-protein- coupled receptors of the endothelial differentiation gene family (S1P receptors-(1-5)). Intracellularly, at least two enzymes, sphingosine kinase and S1P phosphatase, regulate the activity of S1P by governing the phosphorylation status of S1P. It is now well established that S1P is the natural ligand for specific G protein-coupled receptors (GPCRs), hereafter referred to as S1PRs. To date, five members, EDG-1/S1P1, vascular smooth muscle cells and pericytes to migrate around arteries and capillaries and properly reinforce them angiogenesis. DMTF1 cyclin D DMP1 is a pivotal tumor suppressor for Bone health binding myb- both human and murine lung cancers. like DMP1 is essential for normal postnatal transcription chondrogenesis and subsequent factor 1 osteogenesis-bone LEMD3 LEM domain LEMD3 is involved in both BMP (see Bone Health containing 3 112264) and TGF-beta (190180) Activity Gene signaling, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling. Involved in multiple bone disorders. MBTPS1 \membrane- Site-1 protease (S1P) has an essential Bone Health bound function in the conversion of latent, Activity Gene transcription membrane-bound transcription factors to factor their free, active form. In mammals, peptidase, abundant expression of S1P in site 1\“” chondrocytes suggests an involvement in chondrocyte function. Catalyzes the first step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs). Other known substrates are BDNF and ATF6. RPS6KA3 \ribosomal Rsk2 plays an important role in neuronal Bone Health protein S6 plasticity. RSK2 is required for Activity Gene kinase, osteoblast differentiation and function. 90 kDa, Rsk2-null mice develop progressive polypeptide osteopenia due to impaired osteoblast 3\“” function and normal osteoclast differentiation. BCAT1 \branched This gene encodes the cytosolic form of Cell health chain the enzyme branched-chain amino acid Maintenance aminotransferase transaminase. This enzyme catalyzes Gene 1, the reversible transamination of cytosolic\“” branched-chain alpha-keto acids to branched-chain L-amino acids essential for cell growth. CEPT1 choline/ethanolamine Cholinephosphotransferase catalyses Cell health phosphotransferase 1 the final step in the synthesis of Maintenance phosphatidylcholine by the transfer of Gene phosphocholine from CDP-choline to diacylglycerol. The synthesis of phosphatidylethanolamine by ethanolaminephosphotransferase occurs using an analogous reaction. This gene codes for a choline/ethanolaminephosphotransferase. The protein can synthesize either choline- or ethanolamine-containing phospholipids. Phosphatidylcholine is a class of phospholipids called “essential phospholipids DSCR1 Down The DSCR1 (Adapt78) gene is Cell health syndrome transiently induced by stresses to Maintenance critical region temporarily protect cells against further Gene gene 1 potentially lethal challenges. PAPOLA poly(A) Polymerase that creates the 3′ poly(A) Cell health polymerase tail of mRNA's. Also required for the Maintenance alpha endoribonucleolytic cleavage reaction at Gene some polyadenylation sites. HSBP1 heat shock exert cytoprotection and anti-apoptotic Cell health factor binding effects Maintenance protein 1 Gene METAP1 methionyl Protein synthesis is initiated with a Cell health aminopeptidase 1 methionine residue in eukaryotic cells or Maintenance a formylated methionine in prokaryotes, Gene mitochondria, and chloroplasts. For a large subset of proteins, the initiator methionine is cotranslationally removed before further posttranslational modification. The proteolytic removal of N-terminal methionine is catalyzed by a family of enzymes known as methionine aminopeptidases (MetAPs). SGMS1 sphingomyelin Suppresses BAX-mediated apoptosis Cell health synthase 1 and also prevents cell death in response Maintenance to stimuli such as hydrogen peroxide, Gene osmotic stress, elevated temperature and exogenously supplied sphingolipids. May protect against cell death by reversing the stress-inducible increase in levels of proapoptotic ceramide. Required for cell growth STK39 \serine STE20 kinases involved in the regulation Cell health threonine of ion homoeostasis and volume control Maintenance kinase 39 in mammalian cells Gene (STE20/SPS1 homolog, yeast)\“” VCL vinculin Involved in cell adhesion. May be Cell health involved in the attachment of the actin- Maintenance based microfilaments to the plasma Gene membrane. May also play important roles in cell morphology and locomotion. XPNPEP1 \X-prolyl prolyl aminopeptidase (EC 3.4.11.9) is a Cell health aminopeptidase proline-specific metalloaminopeptidase Maintenance (aminopeptidase that specifically catalyzes the removal of Gene P) 1, any unsubstituted N-terminal amino acid soluble\“” that is adjacent to a penultimate proline residue. Because of its specificity toward proline, it has been suggested that X- prolyl aminopeptidase is important in the maturation and degradation of peptide hormones, neuropeptides, and tachykinins, as well as in the digestion of otherwise resistant dietary protein fragments, thereby complementing the pancreatic peptidases. Deficiency of X- prolyl aminopeptidase results in excretion of large amounts of imino- oligopeptides in urine NCAPD3 \non-SMC Regulatory subunit of the condensin II Chomatin condensin II complex, a complex which establishes stability complex, mitotic chromosome architecture and is subunit D3\“” involved in physical rigidity of the chromatid axis. AOF2 amine a family of multiprotein corepressor Chromatin oxidase (flavin complexes that function through modification containing) modifying chromatin structure to keep domain 2 genes silent. The polypeptide composition of these complexes includes a common core of 2 subunits, HDAC1 (601241)/HDAC2 (605164) and the FAD-binding protein AOF2. functions as a histone demethylase and transcriptional corepressor, histone lysine-specific demethylase LSD1 interacts with p53 (191170) to repress p53-mediated transcriptional activation, and to inhibit the role of p53 in promoting apoptosis. HMGN1 high-mobility HMGN1 enhances the rate of heat Chromatin group shock-induced chromatin remodeling in modification nucleosome the HSP70 promoter, thereby leading to binding an increase in the levels of HSP70 domain 1 transcripts during the early stages of heat shock induction. INOC1 INO80 INOC1 defines a subfamily of Chromatin complex SWI2/SNF2 chromatin remodeling modification homolog 1 (S. cerevisiae) proteins. INOC1 displayed ATPase activity specific to double-stranded DNA and exhibited activity on isolated human mononucleosomes. ATP hydrolysis of double-stranded DNA occurred in a linear time course with a calculated Km of 167 microM, similar to that of other ATPases of the SNF2/SWI2 family. PCAF p300/CBP- Histone acetyltransferase; Functions as Chromatin associated a histone acetyltransferase (HAT) to modification factor promote transcriptional activation. Has significant histone acetyltransferase activity with core histones (H3 and H4), and also with nucleosome core particles. RBBP4 retinoblastoma Core histone-binding subunit that may Chromatin binding target chromatin remodeling factors, modification protein 4 histone acetyltransferases and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. RCBTB1 regulator of May be involved in cell cycle regulation Chromatin chromosome by chromatin remodeling. modification condensation (RCC1) and BTB (POZ) domain containing protein 1 TOP2B topoisomerase essential for mammalian neural Chromatin (DNA) II development; catalyses topological modification beta 180 kDa genomic changes essential for chromosome segregation, chromatin reorganization, TSN translin Translin and TRAX have been proposed Chromatin to be involved in DNA recombination, modification chromosomal translocation and mRNA transport and translation. TSNAX translin- Translin and TRAX have been proposed Chromatin associated to be involved in DNA recombination, modification factor X chromosomal translocation and mRNA transport and translation. TSPYL1 TSPY-like 1 chromatin remodeling factor Chromatin modification UTX \ubiquitously Histone H3 methylation at Lys27 (H3K27 Chromatin transcribed methylation) is a hallmark of silent modification tetratricopeptide chromatin, dUTX, specifically repeat, X demethylates di- and trimethylated but chromosome\“” not monomethylated H3K27, dUTX is intimately associated with actively transcribed genes WAPAL wings apart- regulates heterochromatin organization; Chromatin like homolog Wapl is a new regulator of sister modification (Drosophila) chromatid resolution PHC3 polyhomeotic Component of the Polycomb group Chromatin homolog 3 (PcG) multiprotein PRC1 complex, a modification (Drosophila) complex required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; CDYL \chromodomain Proteins encoded by this gene Chromatin protein, Y- superfamily possess a chromodomain, a modification like\“” motif implicated in chromatin binding and gene suppression, and a catalytic domain believed to be involved in histone acetylation. CENPJ centromere structural role for CPAP to maintain Chromatin protein J centrosome integrity and normal spindle modification morphology during cell division. TPK1 thiamin Cofactor pyrophosphokinase 1 biosynthesis gene RFK riboflavin Cofactor kinase biosynthesis gene VNN1 vanin 1 VNN1 gene product is involved in the Cofactor thymus homing of bone marrow cells biosynthesis and in late adhesion steps of thymus gene homing under physiologic, noninflammatory conditions. Recently VNN1 gene upregulation has been linked to increased HDL level The product of CD1c gene is expressed on cortical thymocytes, immature myeloid dendritic cells, subset of normal peripheral B cells and activated T cells P4HA1 \procollagen- When expressed intracellularly or Collagen Tumor proline, 2- exogenously delivered, P4HA1 formation suppressor oxoglutarate significantly inhibited tumor growth in activity gene activity 4- mice. Prolyl 4-hydroxylase (EC gene dioxygenase 1.14.11.2) plays a central role in (proline 4- collagen synthesis. It catalyzes the hydroxylase), formation of 4-hydroxyproline in alpha collagens by hydroxylation of proline polypeptide residues in peptide linkages. The 4- I\“” hydroxyproline residues are essential for the folding of the newly synthesized procollagen polypeptide chain into triple helical molecules. CHST2 carbohydrate CHST1 and CHST2 contribute to the Control of (N- generation of optimal L-selectin ligands inflammation acetylglucosamine- in vascular endothelial cells at sites of activity gene 6-O) inflammation and thus control sulfotransferase 2 inflammation. PAPSS1 3′- 3′-phosphoadenosine 5′-phosphosulfate Detoxification phosphoadenosine (PAPS) synthase (PAPSS) catalyzes the Activity Gene 5′- biosynthesis of PAPS which serves as phosphosulfate the universal sulfonate donor compound synthase 1 for all sulfotransferase reactions. PAPSS forms PAPS in two sequential steps. First inorganic sulfate combines with ATP to form adenosine 5′- phosphosulfate (APS) and pyrophosphate catalyzed by ATP sulfurylase domain and in the second step, APS combines with another molecule of ATP to form PAPS and ADP catalyzed by APS kinase domain. The bifunctional PAPSS1 is comprised of NH2-terminal APS kinase domain (approximately 1-260 aa), and a COOH- terminal ATP sulfurylase domain (approximately 220-623 aa).. Many different endogenous and xenobiotic molecules are substrates for the sulfotransferases; sulfation affects many different physiological processes, including: 1) deactivation and bioactivation of xenobiotics, 2) inactivation of hormones and catecholamines, 3) structure and function of macromolecules, and 4) elimination of end products of catabolism. PAPS is the obligate cosubstrate that is synthesized in tissues to make available an “activated form” of sulfate for the sulfation reaction. PPA2 pyrophosphatase Inorganic pyrophosphates are generated Detoxification (inorganic) 2 as byproducts of many biosynthetic Activity Gene reactions, including DNA and RNA synthesis, fatty acid and amino acid activation, and cyclic nucleotide synthesis. Inorganic pyrophosphatases (EC 3.6.1.1), such as PPA2, maintain the thermodynamic favorability of these reactions by catalyzing the hydrolysis of pyrophosphates into organic phosphates, which are then exported across the cell membrane (Curbo et al., 2006) RTN1 reticulon 1 In the presence of high RTN-1C levels, Detoxification genotoxic drugs become ineffective as a Activity Gene consequence of the cytoplasm translocation of p53 protein, while the silencing of endogenous RTN-1C results in the potentiation of the genotoxic drugs action. Highly present in CNS. CNS stem cells? ATRN attractin in its natural serum form, it mediates the Detoxification mitochondrial spreading of monocytes that becomes Activity Gene, function the focus for the clustering of maintenance nonproliferating T lymphocytes. activity Necessary for proper mitochondrial gene function and suppress oxidative stress. Atrn may play a protective role against environmental toxins PGK1 phosphoglycerate Glycolysis enzyme generating 1 Energy kinase 1 molecule of ATP Generation GLS glutaminase human platelets. It is the major enzyme Energy yielding glutamate from glutamine. generation Significance of the enzyme derives from its possible implication in behavior disturbances in which glutamate acts as a neurotransmitter, platelet glutaminase activity is entirely represented by the phosphate dependent glutaminase or glutaminase I, most probably localized in the mitochondrial platelet fraction and classified by kinetic analysis as a kidney- type form. The following step of the glutamine metabolizing pathway, allowing the entrance of the amino acid skeleton carbons in the Krebs cycle, might be catalyzed by both glutamate dehydrogenase and aspartate transaminase GLUD2 glutamate The following step of the glutamine Energy dehydrogenase 2 metabolizing pathway, allowing the generation entrance of the amino acid skeleton carbons in the Krebs cycle, might be catalyzed by both glutamate dehydrogenase and aspartate transaminase MUT methylmalonyl In mammalian cells only two enzymes Energy Coenzyme A are known to require cobalamin (vitamin generation mutase B12) as a cofactor: methionine synthase, which uses methylcobalamin, and methylmalonyl-coenzyme A (CoA) mutase, which uses 5′-deoxyadenosyl- cobalamin (AdoCbl) Methylmalonyl-CoA mutase (MUT) (EC 5.4.99.2) is a mitochondrial enzyme that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. Methylmalonyl-CoA mutase occupies a key position in the pathway converting propionyl-CoA to succinyl-CoA, with the catabolism of isoleucine, methionine, threonine, and valine, as well as of cholesterol, odd chain fatty acids, thymine, and uracil leading to propionyl-CoA production. The enzyme is, therefore, part of a gluconeogenic pathway for converting amino acids, lipids, and pyrimidines to carbohydrates PPAT phosphoribosyl Phosphopantetheine Energy pyrophosphate adenylyltransferase (PPAT) is an generation amidotransferase essential enzyme in Coenzyme A biosynthesis. Biosynthesis of coenzyme A (CoA) from pantothenic acid (vitamin B5) is an essential universal pathway in prokaryotes and eukaryotes. COASY is a bifunctional enzyme that catalyzes the 2 last steps in CoA synthesis. MTHFR \5,10- Methylenetetrahydrofolate reductase Homocysteine methylenetetrahydrofolate (EC 1.5.1.20) catalyzes the conversion metabolism reductase of 5,10-methylenetetrahydrofolate to 5- (NADPH)\“” methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. MTR 5- The remethylation of homocysteine to Homocysteine methyltetrahydrofolate- form methionine is catalyzed by the metabolism homocysteine cytoplasmic enzyme 5- methyltransferase methyltetrahydrofolate-homocysteine S- methyltransferase (EC 2.1.1.13), which is also called methionine synthase. This enzyme requires methylcobalamin (MeCbl), a derivative of cobalamin, or vitamin B12, for activity. MTRR 5- Methionine is an essential amino acid Homocysteine methyltetrahydrofolate- required for protein synthesis and one metabolism homocysteine carbon metabolism. Its synthesis is methyltransferase catalyzed by the enzyme methionine reductase synthase. Methionine synthase eventually becomes inactive due to the oxidation of its cob(l)alamin cofactor. The protein encoded by this gene regenerates a functional methionine synthase via reductive methylation. It is a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. ADCY7 adenylate Necessary for proper Eucaryotic signal Immune health cyclase 7 transduction in platelets and other blood associated cells including natural killer cells, monocytes, and neutrophils NCKAP1L NCK- Expressed only in cells of hematopoietic Immune associated origin. Health protein 1-like ABCB7 \ATP-binding essential for hematopoiesis Immune cassette, sub- Health family B (MDR/TAP), member 7\“” AHI1 Abelson expression of mouse and human AHI1 Immune helper was highest in the most primitive types Health integration of normal hematopoietic cells and was site 1 downregulated during early differentiation. This indicates that early precursors of blood cells are likely present in the peripheral blood. CD164 \CD164 myeloid cells, T cells, epithelial cells, Immune molecule, bone marrow stroma cells; adhesion Health sialomucin\“” molecule haem progenitor cells to stroma CD200 CD200 Normal brain and B-cell lines Immune molecule Health CD74 \CD74 B cells, macrophages, monocytes, MHC Immune health molecule, class II positive cells major histocompatibility complex, class II invariant chain\“” CD83 CD83 Activated B cells, activated T cells, Immune health molecule circulating dendritic cells; CD8A CD8a The CD8 antigen is a cell surface Immune health molecule glycoprotein found on most cytotoxic T lymphocytes that mediates efficient cell- cell interactions within the immune system. The CD8 antigen, acting as a coreceptor, and the T-cell receptor on the T lymphocyte recognize antigen displayed by an antigen presenting cell (APC) in the context of class I MHC molecules. Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+ T cells, since they express the CD8 glycoprotein at their surface. Through interaction with helper T cells, these cells can be transformed into regulatory T cells, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis CERK ceramide Catalyzes specifically the Immune kinase phosphorylation of ceramide to form Health ceramide 1-phosphate. Ceramide 1- Phosphate, a Mediator of Phagocytosis, might function as components of a ‘rheostat’ that regulates immune cell functions, including mast cell responsiveness, neutrophil and macrophage priming, chemotaxis, and survival of many types of immune cells. CIAPIN1 cytokine CIAPIN1, a necessary molecule for Immune induced hematopoiesis that mediates Health apoptosis antiapoptotic effects of various inhibitor 1 cytokines. CIITA \calss II, Highly present in B-lymphocytes. This Immune health major gene encodes a protein with an acidic histocompatibility transcriptional activation domain, 4 complex, LRRs (leucine-rich repeats) and a GTP transactivator\ binding domain. The protein is located in “” the nucleus and acts as a positive regulator of class II major histocompatibility complex gene transcription, and is referred to as the “master control factor” for the expression of these genes. Mutations (lack of fuction) in this gene have been associated with bare lymphocyte syndrome type II (also known as hereditary MHC class II deficiency or HLA class II-deficient combined immunodeficiency), increased susceptibility to rheumatoid arthritis, multiple sclerosis, and possibly myocardial infarction. CLEC10A \C-type lectin Probable role in regulating adaptive and Immune domain family innate immune responses. Binds in a Health 10, member calcium-dependent manner to terminal A\“” galactose and N-acetylgalactosamine units, linked to serine or threonine. CPNE3 copine III copine III were expressed in the more Immune immature neutrophil precursors Health CPVL \carboxypeptidase, CPVL protein expression was induced Immune vitellogenic- during maturation of monocytes into Health like\“” macrophages. CTNNB1 \catenin Hematopoietic stem cells (HSCs) have Immune (cadherin- the ability to renew themselves and to Health associated give rise to all lineages of the blood. protein), beta Reya et al. (2003) showed that the WNT 1, 88 kDa\“” signaling pathway has an important role in this process. Overexpression of activated beta-catenin expands the pool of HSCs in long-term cultures by both phenotype and function, beta-catenin is essential for fate decisions of skin stem cells: in the absence of beta-catenin, stem cells failed to differentiate into follicular keratinocytes and instead adopted an epidermal fate CTSC cathepasin C Needed for activity and stability of Immune neutrophil-derived serine proteases. Health CYFIP2 cytoplasmic Necessary for T-cell adhesion function Immune FMR1 Health interacting protein 2 DPP8 dipeptidyl- involve in immune functions Immune peptidase 8 Health DPP9 dipeptidyl- involve in immune functions Immune peptidase 9 Health DPYSL2 dihydropyrimidinase- involved in T-cell polarization and Immune like 2 migration. Health DUSP5 dual Mkp5-deficient cells produced greatly Immune specificity enhanced levels of proinflammatory Health phosphatase 5 cytokines during innate immune responses and exhibited greater T-cell activation than their wildtype counterparts. However, Mkp5-deficient T cells proliferated poorly upon activation, which resulted in increased resistance to experimental autoimmune encephalomyelitis. By contrast, Mkp5- deficient CD4+ (186940) and CD8+ (186910) effector T cells produced significantly increased levels of cytokines compared with wildtype cells, which led to much more robust and rapidly fatal immune responses to secondary infection with lymphocytic choriomeningitis virus. Zhang et al. (2004) concluded that MKP5 has a principal function in both innate and adaptive immune responses. EDG1 \endothelial Adaptive immunity depends on T-cell Immune differentiation, exit from the thymus and T and B cells Health sphingolipid travelling between secondary lymphoid G-protein- organs to survey for antigens. After coupled activation in lymphoid organs, T cells receptor, 1\“” must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. FCRL5 Fc receptor- May be involved in B-cell development Immune like 5 and differentiation in peripheral lymphoid Health organs and may be useful markers of B- cell stages. May have an immunoregulatory role in marginal zone B-cells. FER fer (fps/fes Fps/Fes modulates the innate immune Immune related) response of macrophages to LPS, in Health tyrosine part, by regulating internalization and kinase down-regulation of the TLR4 receptor (phosphoprotein complex. Fps/Fes and Fer are members NCP94) of a distinct subfamily of cytoplasmic protein tyrosine kinases that have recently been implicated in the regulation of innate immunity, evidence for functional redundancy between Fps and Fer kinases in regulating hematopoiesis. FLT3 fms-related CD135 is a cytokine receptor expressed Immune tyrosine on the surface of hematopoietic Health kinase 3 progenitor cells. Signaling through CD135 plays a role in cell survival, proliferation, and differentiation. CD135 is important for lymphocyte (B cell and T cell) development, but not for the development of other blood cells (myeloid development). NKTR natural killer- The natural killer triggering receptor Immune tumor (NKTR) is involved in the recognition of Health recognition tumor cells by large granular sequence lymphocytes (LGLs) (Frey et al., 1991; Anderson et al., 1993). LGLs are a subpopulation of white blood cells that have the ability to kill target tumor cells by an MHC-independent mechanism. The protein product of the NKTR gene is present on the surface of LGLs and facilitates their binding to tumor targets. The gene codes for a protein of 150,000 Da, with a unique amino acid structure consisting of a 58-amino acid hydrophobic amino terminus followed by a cyclophilin-related domain. PABPC4 \poly(A) might be necessary for regulation of Immune binding stability of labile mRNA species in Health protein, activated T cells. cytoplasmic 4 (inducible form)\“” PAG1 phosphoprotein Absence of external stimuli, the PAG- Immune health associated Csk complex transmits negative with regulatory signals and thus may help to glycosphingolipid keep resting T cells in a quiescent state. microdomains 1 PAG-CSK complex increases the signaling threshold required for initiating an immune response, thus helping to keep lymphocytes in a resting state. ADRBK2 \adrenergic, Specifically phosphorylates the agonist- Immune health beta, receptor occupied form of the beta-adrenergic kinase 2\“” and closely related receptors, in leukocytes from patients with active relapsing-remitting multiple sclerosis (MS) or with secondary progressive MS, GRK2 levels are significantly reduced, probable role in immune Maintenance and health GFI1 growth factor Gfi1 maintained hematopoietic stem cell Immune health independent 1 self-renewal, multilineage differentiation, and efficient reconstitution of hematopoiesis in transplanted hosts by restricting stem cell proliferation GPR34 G protein- GPR34 is the functional mast cell lysoPS Immune health coupled receptor. Lysophosphatidyl-L-serine receptor 34 (lysoPS) is thought to be an immunological regulator GPR44 G protein- This receptor also called, CRTH2 is a Immune health coupled receptor for PGD2, PGD2 functions as a receptor 44 neuromodulator as well as a trophic factor in the central nervous system. PGD2 is also involved in smooth muscle contraction/relaxation and is a potent inhibitor of platelet aggregation, receptor for prostaglandin (PG) D(2), which is a major mast cell product released during the allergic response. CRTH2 mediates the chemotaxis of eosinophils, basophils, and Th2 lymphocytes HHEX hematopoietically Transcriptional repressor. May play a Immune health expressed role in hematopoietic differentiation. homeobox ID2 \inhibitor of Id2 has an essential role in the Immune health DNA binding generation of peripheral lymphoid 2, dominant organs and NK cells. D (inhibitor of DNA negative binding) HLH proteins lack a basic DNA- helix-loop- binding domain but are able to form helix protein\“” heterodimers with other HLH proteins, thereby inhibiting DNA binding, importance of Id2 in regulating gene expression by CD8(+) T cells and the magnitude of effector responses, suggesting a mechanism involving Id protein- and E protein-mediated survival and differentiation of mature T cells, helix-loop-helix (HLH) transcription factor Id2 (inhibitor of DNA binding/differentiation 2) acts as a molecular switch in development of Langerhans cells (LCs), the cutaneous contingent of dendritic cells (DCs), and of specific DC subsets and B cells. IL10RA \interleukin 10 The protein encoded by this gene is a Immune health receptor, receptor for interleukin 10. This protein is alpha\“” structurally related to interferon receptors. It has been shown to mediate the immunosuppressive signal of interleukin 10, and thus inhibits the synthesis of proinflammatory cytokines. This receptor is reported to promote survival of progenitor myeloid cells through the insulin receptor substrate- 2/PI 3-kinase/AKT pathway. Activation of this receptor leads to tyrosine phosphorylation of JAK1 and TYK2 kinases. IL7R interleukin 7 This protein has been shown to play a Immune health receptor critical role in the V(D)J recombination during lymphocyte development. This protein is also found to control the accessibility of the TCR gamma locus by STAT5 and histone acetylation. Knockout studies in mice suggested that blocking apoptosis is an essential function of this protein during differentiation and activation of T lymphocytes. The functional defects in this protein may be associated with the pathogenesis of the severe combined immunodeficiency (SCID). Receptor for interleukin-7. Also acts as a receptor for thymic stromal lymphopoietin IRF8 interferon ICSBP in regulating the proliferation Immune health regulatory and differentiation of hematopoietic factor 8 progenitor cells, antiviral responses associated with impaired production of IFN-gamma ITK IL2-inducible Tec kinases Itk and Rlk provide Immune health T-cell kinase important signals for terminal maturation, efficient cytokine production, and peripheral survival of NKT cells. This gene encodes an intracellular tyrosine kinase expressed in T-cells. The protein contains both SH2 and SH3 domains which are often found in intracellular kinases. It is thought to play a role in T- cell proliferation and differentiation. JAK1 Janus kinase Tyrosine kinase of the non-receptor Immune health 1 (a protein type, involved in the IFN- tyrosine alpha/beta/gamma signal pathway. kinase) Kinase partner for the interleukin (IL)-2 receptor. The Janus kinase-signal transducer and activator of transcription (Jak-Stat) pathway stands as a paradigm of how diverse extracellular signals can elicit rapid changes in gene expression in specific target cells. This pathway is widely used by members of the cytokine receptor superfamily, including those for the clinically important cytokines granulocyte colony- stimulating factor (G-CSF), erythropoietin, thrombopoietin, the interferons, and numerous interleukins, which makes it central to hematopoietic cell biology and hematologic therapy alike. Impaired lymphoid development in the absensce of JAK1 JMJD1A jumonji Jmjd1a and Jmjd2c histone H3 Lys 9 Immune health domain demethylases regulate self-renewal in containing 1A embryonic stem cells. JMJD2C jumonji Jmjd1a and Jmjd2c histone H3 Lys 9 Immune health domain demethylases regulate self-renewal in containing 2C embryonic stem cells. KIR2DS2 \killer cell Killer-cell immunoglobulin-like receptors Immune health immunoglobulin- (KIRs), are a family of cell surface like proteins found on important cells of the receptor, two immune system called natural killer (NK) domains, cells. They regulate the killing function of short these cells by interacting with MHC class cytoplasmic I molecules, which are expressed on all tail, 2\“” cell types. This interaction allows them to detect virally infected cells or tumor cells that have a characteristic low level of Class I MHC on their surface. Most KIRs are inhibitory, meaning that their recognition of MHC suppresses the cytotoxic activity of their NK cell. Only a limited number of KIRs have the ability to activate cells. This gene is an activating receptor. KLRC1 \killer cell Natural killer (NK) cells are lymphocytes Immune health lectin-like that can mediate lysis of certain tumor receptor cells and virus-infected cells without subfamily C, previous activation. They can also member 1\“” regulate specific humoral and cell- mediated immunity. NK cells preferentially express several calcium- dependent (C-type) lectins, which have been implicated in the regulation of NK cell function. L3MBTL3 l(3)mbt-like 3 H-L(3)MBT protein, whose deletion is Immune health (Drosophila) predicted to be responsible for myeloid hematopoietic malignancies, tumor suppressor gene. MEMO1 mediator of Highly present in NK cells and other Immune health cell motility 1 hematopoeitic cells NAGA \N- Highly present in monocytes (Ascenta) Immune health acetylgalactos what are the implications? lysosomal aminidase, glycohydrolase that cleaves alpha-N- alpha-\“” acetylgalactosaminyl moieties from glycoconjugates. NDFIP1 Nedd4 family Ndfip1 protein promotes the function of Immune health interacting itch ubiquitin ligase to prevent T cell protein 1 activation and T helper 2 cell-mediated inflammation. NR1D2 \nuclear Heme as the ligand Immune health receptor subfamily 1, group D, member 2\“” PRNP \prion protein PrPc is expressed on hematopoietic Immune health Red blood (p27-30) cells, including erythroid precursors. cell health (Creutzfeldt- Prion protein is expressed on long-term Jakob repopulating hematopoietic stem cells disease, and is important for their self-renewal. Gerstmann- PrP is a marker for long-term Strausler- hematopoietic stem cells. Prion protein Scheinker expression may be involved in both the syndrome, metabolism of copper and resistance to fatal familial oxidative stress, neuroprotective role of insomnia)\“” cellular prion protein (PrPC) rion protein interferes with divalent metal Mn uptake and protects against Mn-induced oxidative stress PSCD1 \pleckstrin Members of this family appear to Immune health homology, mediate the regulation of protein sorting Sec7 and and membrane trafficking. The PSCD1 coiled-coil is highly expressed in natural killer and domains peripheral T cells, and regulates the 1(cytohesin adhesiveness of integrins at the plasma 1)\“” membrane of lymphocytes. PTGER4 prostaglandin This receptor can activate T-cell factor Immune health E receptor 4 signaling. It has been shown to mediate (subtype EP4) PGE2 induced expression of early growth response 1 (EGR1), regulate the level and stability of cyclooxygenase-2 mRNA, and lead to the phosphorylation of glycogen synthase kinase-3. Knockout studies in mice suggest that this receptor may be involved in the neonatal adaptation of circulatory system, osteoporosis, as well as initiation of skin immune responses. Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. Has a relaxing effect on smooth muscle. May play an important role in regulating renal hemodynamics, intestinal epithelial transport, adrenal aldosterone secretion, and uterine function. PTPN11 \protein Shp-2 is a widely expressed nonreceptor Immune health tyrosine protein tyrosine phosphatase that phosphatase, participates early in hematopoietic non-receptor development. type 11 (Noonan syndrome 1)\“” PTPN22 \protein This gene encodes a protein tyrosine Immune health tyrosine phosphatase which is expressed phosphatase, primarily in lymphoid tissues. This non-receptor enzyme associates with the molecular type 22 adapter protein CBL and may be (lymphoid)\“” involved in regulating CBL function in the T-cell receptor signaling pathway. PTPRC \protein This gene is specifically expressed in Immune health tyrosine hematopoietic cells. This PTP has been phosphatase, shown to be an essential regulator of T- receptor type, and B-cell antigen receptor signaling. It C\“” functions through either direct interaction with components of the antigen receptor complexes, or by activating various Src family kinases required for the antigen receptor signaling. This PTP also suppresses JAK kinases, and thus functions as a regulator of cytokine receptor signaling. RASSF5 Ras Potential tumor suppressor. Seems to Immune health association be involved in lymphocyte adhesion by (RalGDS/AF- linking RAP1A activation upon T cell 6) domain receptor or chemokine stimulation to family 5 integrin activation. Isoform 2 stimulates lymphocyte polarization and the patch- like distribution of ITGAL/LFA-1, resulting in an enhanced adhesion to ICAM1. Together with RAP1A may participate in regulation of microtubule growth. The association of isoform 2 with activated RAP1A is required for directional movement of endothelial cells during wound healing RFX5 \regulatory MHC class II molecules play a key role Immune health factor X, 5 in the immune system. They present (influences exogenous antigenic peptides to the HLA class II receptor of CD4+ T-helper lymphocytes, expression)\“” thereby triggering the antigen-specific T- cell activation events required for the initiation and sustenance of immune responses.. Activates transcription from class II MHC promoters. Differentiation of hematopoietic stem and progenitors cells is an intricate process controlled in large part at the level of transcription. new transcriptional regulators of megakaryopoiesis. SENP6 SUMO1/sentrin important in adult hematopoietic self- Immune health specific renewal peptidase 6 SERPINB9 \serpin The intracellular granzyme B inhibitor, Immune health peptidase proteinase inhibitor 9, is up-regulated inhibitor, during accessory cell maturation and clade B effector cell degranulation, and its (ovalbumin), overexpression enhances CTL (cytotoxic member 9\“” lymphocyte) potency, the presence and subcellular localization of PI-9 in leukocytes and DCs are consistent with a protective role against ectopic or misdirected grB during an immune response. SOX4 SRY (sex Sox4 contribute to the survival and Immune health determining proliferation of pro-B cells in response to region Y)-box 4 extracellular signals. SPEN \spen The ability of Ott1 to affect Immune health homolog, hematopoietic cell fate and expansion in transcriptional multiple lineages is a novel attribute for regulator a spen family member and delineates (Drosophila)\“” Ott1 from other known effectors of hematopoietic development. SYBL1 synaptobrevin- VAMP-7 is a crucial component of Immune health like 1 granzyme B release and target cell killing in the NK cell TMPO thymopoietin It is possible that TCERG1 interacts with Immune health the nascent transcript (or RNP) and directly alters splicing decisions. This could be consistent with independent effects on transcription elongation and alternative processing. Alternatively, TCERG1 could work at VNN1 vanin 1 VNN1 gene product is involved in the Immune health thymus homing of bone marrow cells and in late adhesion steps of thymus homing under physiologic, noninflammatory conditions. Recently VNN1 gene upregulation has been linked to increased HDL level The product of CD1c gene is expressed on cortical thymocytes, immature myeloid dendritic cells, subset of normal peripheral B cells and activated T cells ZFX \zinc finger Zfx controls the self-renewal of Immune health protein, X- embryonic and hematopoietic stem cells. linked\“” Zfx as a shared transcriptional regulator of ESC and HSC, suggesting a common genetic basis of self-renewal in embryonic and adult SC. ZNF317 zinc finger ZNF317 may play an important role in Immune health Red blood protein 317 erythroid maturation and lymphoid cell health proliferation ZNF589 zinc finger Characterization of SZF1 implicates its Immune health protein 589 role in hematopoiesis. OGT O-linked N- The regulation of topoisomerase I (topo Immune acetylglucosamine I) activity is of prime importance for gene Health (GlcNAc) expression. It participates in DNA transferase replication, transcription, recombination, (UDP-N- and DNA repair, and serves as a target acetylglucosamine: for anticancer drugs. Many proteins and polypeptide- enzymes are modified by O-linked beta- N- N-acetylglucosamine (O-GlcNAc), which acetylglucosaminyl exerts profound effects on their function. transferase) OGT is a central factor for T- and B- lymphocytes activation.. OGT participation in intracellular glycosylation is essential for embryonic stem cell viability PIK3R1 \phosphoinositide- Important in adult hematopoietic self- Immune 3-kinase, renewal Health regulatory subunit 1 (p85 alpha)\“” NKRF NF-kappaB Interacts with a specific negative Inflammation repressing regulatory element (NRE) 5′- control factor AATTCCTCTGA-3′ to mediate transcriptional repression of certain NK- kappa-B responsive genes. NF-κB- repressing factor (NRF) is a constitutively expressed nuclear transcription factor that binds to beta interferon (IFN-β), interleukin-8 (IL-8), and inducible nitric oxide synthase (iNOS) promoters and represses the basal transcription of these genes NR3C1 \nuclear The glucocorticoid receptor (GR) is a Inflammation receptor ligand-dependent transcription factor control subfamily 3, belonging to the nuclear hormone group C, receptor superfamily. Due to its almost member 1 ubiquitous expression, GR plays an (glucocorticoid important role in many physiological and receptor)\“” pathological processes. These include regulation of homeostasis, adaptation to stress, and modulation of central nervous system. In addition, GR is a major modulator of the immune system due to its proficient anti-inflammatory and immunosuppressive activity; and its function is important for proper regulation of many physiological processes. ZCCHC11 \zinc finger, ZCCHC11 is a unique TLR signal Inflammation CCHC regulator, which interacts with TIFA after control domain LPS treatment and suppresses the containing TRAF6-dependent activation of NF- 11\“” kappaB. SIRT1 sirtuin (silent Longevity gene Longevity mating type gene information regulation 2 homolog) 1 (S. cerevisiae) YTHDF2 \YTH domain A polymorphism of the YTHDF2 gene Longevity family, (1p35) located in an Alu-rich genomic gene member 2\“” domain is associated with human longevity. AP15 apoptosis Survival gene or anti-apoptotic gene Longevity inhibitor 5 gene ARNT aryl Bmal1-null mice lose circadian Longevity hydrocarbon rhythmicity but also display tendon gene receptor calcification and decreased activity, nuclear body weight, and longevity translocator FRAP1 FK506 a gene expression signature associated Longevity binding with mammalian target of rapamycin gene protein 12- (mTOR) activity that was down-regulated rapamycin with age but preserved by CR in both associated WAT and heart, mammalian cells the protein 1 mammalian TOR (mTOR) pathway plays a significant role in determining both resting oxygen consumption and oxidative capacity, mTOR activity may play an important role in determining the relative balance between mitochondrial and non-mitochondrial sources of ATP generation. HSPA9 heat shock this member of the hsp70 family governs Longevity 70 kDa protein the longevity of worms and thus there gene 9 (mortalin) are common pathways that determine mammalian and worm longevity POLG2 \polymerase Mitochondrial polymerase processivity Mitochondrial (DNA subunit. Stimulates the polymerase and DNA Health directed), exonuclease activities, and increases gamma 2, the processivity of the enzyme. Binds to accessory sc-DNA. subunit\“” OPA1 optic atrophy Mitochondrial health is defined by Mitochondrial 1 (autosomal various parameters including fusion and Health dominant) fission events. In older cells, giant mitochondria accumulates. This is because of insufficient autophagy. These giants don't fuse with each other or with normal mitochondria and it was noticed that OPA1 is reduced in these giant mitochondria, mitochondria fuse and divide to change their morphology in response to a multitude of signals. During the past decade, work using yeast and mammalian cells has identified much of the machinery required for fusion and division, including the dynamin-related GTPases-- mitofusins (Fzo1p in yeast) and OPA1 (Mgm1p in yeast) for fusion and Drp1 (Dnm1p) for division. Mitochondrial fusion requires coordinated fusion of the outer and inner membranes. This process leads to exchange of contents, controls the shape of mitochondria, and is important for mitochondrial function. OPA1 is a major organizer of the mitochondrial inner membrane and is required for the maintenance of cristae integrity. As the loss of OPA1 committed cells to apoptosis without any other stimulus. Olichon et al. (2003) proposed that OPA1 is involved in the sequestration of cytochrome c, and that OPA1 may be a target for mitochondrial apoptotic effectors. PDSS2 \prenyl PDSS2 gene, which encodes a subunit Mitochondrial (decaprenyl) of decaprenyl diphosphate synthase, the Health diphosphate first enzyme of the CoQ(10) biosynthetic synthase, pathway. subunit 2\“” MFN1 mitofusin 1 The regulated equilibrium between Mitochondrial mitochondrial fusion and fission is Health essential to maintain integrity of the organelle. Mechanisms of mitochondrial fusion are largely uncharacterized in mammalian cells. It is unclear whether OPA1, a dynamin-related protein of the inner membrane mutated in autosomal dominant optic atrophy, participates in fusion or fission. OPA1 promoted the formation of a branched network of elongated mitochondria, requiring the integrity of both its GTPase and C- terminal coiled-coil domain. Stable reduction of OPA1 levels by RNA interference resulted in small, fragmented, and scattered mitochondria. Levels of OPA1 did not affect mitochondrial docking, but they correlated with the extent of fusion as measured by polyethylene glycol mitochondrial fusion assays. A genetic analysis proved that OPA1 was unable to tubulate and fuse mitochondria lacking the outer membrane mitofusin 1 but not mitofusin 2. Our data show that OPA1 functionally requires mitofusin 1 to regulate mitochondrial fusion and reveal a specific functional difference between mitofusin 1 and 2. MTRF1L mitochondrial Mitochondrial translational Health release factor 1-like NDUFC2 \NADH Accessory subunit of the mitochondrial Mitochondrial dehydrogenase membrane respiratory chain NADH Health (ubiquinone) dehydrogenase (Complex I), that is 1, believed to be not involved in catalysis. subcomplex Complex I functions in the transfer of unknown, 2, electrons from NADH to the respiratory 14.5 kDa\“” chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. NDUFS1 \NADH Core subunit of the mitochondrial Mitochondrial dehydrogenase membrane respiratory chain NADH Health (ubiquinone) dehydrogenase (Complex I) that is Fe—S protein believed to belong to the minimal 1.75 kDa assembly required for catalysis. (NADH- Complex I functions in the transfer of coenzyme Q electrons from NADH to the respiratory reductase)\“” chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (By similarity). This is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized. SDHD \succinate Complex II of the respiratory chain, Mitochondrial dehydrogenase which is specifically involved in the Health complex, oxidation of succinate, carries electrons subunit D, from FADH to CoQ. The complex is integral composed of four nuclear-encoded membrane subunits and is localized in the protein\“” mitochondrial inner membrane. ENC1 ectodermal- Highly present in neuronal cells (and Nervous neural cortex brain tissues from Ascenta-almost System Health (with BTB-like absent in other tissues) and involved in domain) neuronal differentiation. Likely a Redox controlling protein ADNP activity- Involved in proper lipid metabolism, Nervous dependent coagulation as well as in neurogenesis. System Health neuroprotector Multiple Roles in Neuronal Differentiation and Maintenance, neuroprotective protein AGTPBP1 ATP/GTP zinc carboxypeptidase that contains Nervous binding nuclear localization signals and an System Health protein 1 ATP/GTP-binding motif that was initially cloned from regenerating spinal cord neurons of the mouse. Role in preventing neurodegeneration. OAT ornithine OAT encodes the mitochondrial enzyme Nervous aminotransferase ornithine aminotransferase, which is a system health (gyrate key enzyme is the pathway that converts atrophy) arginine and ornithine into the major excitatory and inhibitory neurotransmitters glutamate and GABA. Vitamin B6 dependent enzyme. PTDSS1 Phosphatidylserine Phosphatidylserine (PS or PtdSer) is a Nervous synthase 1 phospholipid nutrient found in fish, green system health leafy vegetables, soybeans, and rice, and is essential for the normal functioning of neuronal cell membranes, activating protein kinase C (PKC), which has been shown to be involved in memory function. PS has been investigated in a small number of double-blind placebo trials and has been shown to increase memory performance in the elderly. Because of the potential cognitive benefits of phosphatidylserine, the substance is sold as a dietary supplement to people that believe they can benefit from an increased intake. SPOCK2 \sparc/osteonectin, May participate in diverse steps of Nervous cwcv neurogenesis system health and kazal-like domains proteoglycan (testican) 2\“” ADSS adenylosuccinate carries out the first of a 2-step sequence Nucleotide synthase in the biosynthesis of AMP from IMP. Biosynthesis Plays an important role in the de novo pathway of purine nucleotide biosynthesis. AMP, is a nucleotide that is found in RNA. DCTD dCMP Supplies the nucleotide substrate for Nucleotide deaminase thymidylate synthetase which is the Biosynthesis enzyme used to generate thymidine monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair. HPRT1 hypoxanthine HPRT1 has a central role in the Nucleotide phosphoribosyltransferase generation of purine nucleotides through biosynthesis 1 (Lesch- the purine salvage pathway. HPRT1 Nyhan catalyzes conversion of hypoxanthine to syndrome) inosine monophosphate and guanine to guanosine monophosphate via transfer of the 5-phosphoribosyl group from 5- phosphoribosyl 1-pyrophosphate PRPS1 phosphoribosyl Phosphoribosylpyrophosphate Nucleotide pyrophosphate synthetase (PRPS; EC 2.7.6.1) biosynthesis synthetase 1 catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl- 1-pyrophosphate, which is necessary for the de novo and salvage pathways of purine and pyrimidine biosynthesis CMPK cytidylate Uridine monophosphate (UMP)/cytidine Nucleotide Mitochondrial kinase monophosphate (CMP) kinase (EC Biosynthesis Health 2.7.4.4) catalyzes the phosphoryl transfer from ATP to UMP, CMP, and deoxy-CMP (dCMP), resulting in the formation of ADP and the corresponding nucleoside diphosphate. These nucleoside diphosphates are required for cellular nucleic acid synthesis. Enzyme deficiency in the salvage pathway of deoxyribonucleotide synthesis in mitochondria can cause mtDNA depletion syndromes. Maintenance of mitochondrial health. ABCD3 \ATP-binding Peroxisome biogenesis Peroxisome cassette, sub- Health family D (ALD), member 3\“” ABCD4 \ATP-binding Peroxisome biogenesis Peroxisome cassette, sub- Health family D (ALD), member 4\“” PEX12 peroxisomal Peroxisome biogenesis Health factor 12 PEX3 peroxisomal Peroxisome biogenesis Health factor 3 RABGAP1L RAB GTPase Lower levles in platelet dysfunction Platelet health activating protein 1-like CANX calnexin Calcium-binding protein that interacts Protein quality with newly synthesized glycoproteins in control the endoplasmic reticulum. It may act in assisting protein assembly and/or in the retention within the ER of unassembled protein subunits. It seems to play a major role in the quality control apparatus of the ER by the retention of incorrectly folded proteins. CLPX ClpX Clp ATPases are protein machines Protein quality caseinolytic involved in protein degradation. The control peptidase X ClpXP ATPase-protease complex is a homolog (E. coli) major component of the protein quality control machinery in the cell. DERL1 \Der1-like Derlin-1 is an important factor for the Protein quality domain extraction of certain aberrantly folded control family, proteins from the mammalian ER. member 1\“” Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins. May act by forming a chann DNAJA1 \DnaJ Human DnaJ 2 (Hdj-2) is a co- Protein quality (Hsp40) chaperone of heat shock cognate 70 control homolog, (Hsc70) which is localized to the subfamily A, cytosolic face of the ER. Necessary for member 1\“” proper folding of proteins and therefore proper functions of various proteins. EDEM3 \ER enhances glycoprotein endoplasmic Protein quality degradation reticulum-associated degradation and control enhancer, mannose trimming, accelerates ERAD of mannosidase misfolded glycoproteins. alpha-like 3\“” OMA1 \OMA1 The integrity of the inner membrane of Protein quality homolog, zinc mitochondria is maintained by a control metallopeptidase membrane-embedded quality control S. cerevisiae)\ system that ensures the removal of “” misfolded membrane proteins. Two ATP-dependent AAA proteases with catalytic sites at opposite membrane surfaces are key components of this proteolytic system, identify Oma1 as a novel component of the quality control system in the inner membrane of mitochondria. Mitochondrial protease CTSO cathepsin O normal cellular protein degradation and Protein quality tumover control HSP90AB1 \heat shock HSP90's function in the regulation and Protein quality protein 90 kDa correct folding of at least 100 control alpha proteins[26] allows it to refold and/or (cytosolic), degrade these products before they class B trigger cell death. They participate in the member 1\“” regulation of the stress response [2, 3] and, when associated with other co- chaperones, function in correctly folding newly synthesized proteins, stabilizing and refolding denatured proteins after stress, preventing misfolding and aggregation of unfolded or partially folded proteins, and assisting in protein transport across the endoplasmic reticulum (ER) and organellar membranes [4-8]. HSP90 members have key roles in the maturation of signal transduction proteins, like hormone receptors, various kinases, nitric oxide synthase and calcineurin HSPBAP1 HSPB (heat Protein quality shock 27 kDa) control associated protein 1 NGLY1 N-glycanase 1 N-glycanase is a highly conserved Protein quality enzyme that catalyzes deglycosylation control of misfolded N-linked glycoproteins by cleaving the glycan chain before the proteins are degraded by the proteasome SACS spastic ataxia The presence of heat-shock domains Protein quality of Charlevoix- suggested a function for sacsin in control Saguenay chaperone-mediated protein folding. (sacsin) SELS selenoprotein S SEPS1 gene helps in ridding the cell of Protein quality misfolded proteins, preventing it from control accumulating and subsequently resulting to inflammation. SEPS1 as a type of “garbage truck” that helps clear faulty proteins that accumulate in cells when they are placed under stress, causing inflammation to develop. ST13 suppression Hip facilitates may facilitate the Protein quality of chaperone function of Hsc/Hsp70 in control tumorigenicity protein folding and repair, and in 13 (colon controlling the activity of regulatory carcinoma) proteins such as steroid receptors and (Hsp70 regulators of proliferation or apoptosis. interacting protein) PDIA6 \protein Formation and rearrangement of Protein quality disulfide disulfide bonds during the correct folding control isomerase of nascent proteins is modulated by a family A, family of enzymes known as thiol member 6\“” isomerases, which include protein disulfide isomerase (PDI), PDCL phosducin-like most members of the phosducin family Protein quality act as co-chaperones with the cytosolic control chaperonin complex (CCT) to assist in the folding of a variety of proteins from their nascent polypeptides PDCL3 phosducin-like 3 most members of the phosducin family Protein quality act as co-chaperones with the cytosolic control chaperonin complex (CCT) to assist in the folding of a variety of proteins from their nascent polypeptides AGA aspartylglucos key enzyme in the catabolism of N- Protein quality; aminidase linked oligosaccharides of glycoproteins. Nervous It cleaves the asparagine from the system health residual N-acetylglucosamines as one of the final steps in the lysosomal breakdown of glycoproteins. Needed for proper folding of proteins, particularly in the nervous system ABCB10 \ATP-binding a mitochondrial inner membrane Red blood cell cassette, sub- erythroid transporter involved in heme health family B biosynthesis (MDR/TAP), member 10\“” CAPRIN2 caprin family Involved in regulation of growth as Red blood cell member 2 erythroblasts shift from a highly health proliferative state towards their terminal phase of differentiation. CYBRD1 cytochrome b Cybrd1 (duodenal cytochrome b) is not Red blood cell reductase 1 necessary for dietary iron absorption in health mice. Likely participates in enhanced iron demand due to erythropoesis, ay be involved in extracellular ascorbate recycling in erythrocyte membranes. EDRF1 Erythroid Transcription factor involved in erythroid Red blood cell differentiation- differentiation. Involved in transcriptional health related activation of the globin gene. factor 1 ERMAP erythroblast Human Ermap is highly expressed in Red blood cell membrane- erythroid tissues and the protein health associated localizes to the plasma membrane, protein particularly in sites of cell contact, and (Scianna “cytoplasmic bodies.” Ermap expression blood group) was restricted to fetal and adult erythroid tissues ETS1 v-ets ETS is responsible for erythroblast and Red blood cell Immune erythroblastos fibroblast transformation. Critical for health Health is virus E26 maturation of the T Cells. Tumor oncogene suppressor. homolog 1 (avian) FLVCR1 feline Exports cytoplasmic heme. May be Red blood cell leukemia virus required to protect developing erythroid health subgroup C cells from heme toxicity. cellular receptor 1 ADD3 adducin 3 ADD3 may have a role in erythroblasts Red blood cell (gamma) and play an earlier role in erythropoiesis, health hypertension. IKZF1 IKAROS structure of a chromatin remodeling Red blood cell family zinc complex (PYR complex) with Ikaros as health finger 1 its DNA binding subunit that is (Ikaros) specifically present in adult murine and human hematopoietic cells. Ikaros is involved in human adult or fetal erythroid differentiation as well as in the commitment between erythroid and myeloid cells. MAEA macrophage The association of erythroblasts with Red blood cell erythroblast macrophages plays a central role in the health attacher terminal maturation and enucleation of erythroblasts. MAEA mediates attachment of erythroblasts to macrophages. MYB v-myb c-Myb is strictly required for expression Red blood cell myeloblastosis of the c-Kit receptor in erythroid cells. health viral The transcription factor c-Myb is oncogene expressed at high levels in immature homolog progenitors of all hematopoietic lineages (avian) and is involved in the regulation of proliferation, differentiation, and survival, role for c-Myb as a factor promoting commitment to erythropoiesis and progression from early to late stages of differentiation (FIG. 6). We have shown that this function of c-Myb is probably not related to the cell cycle but rather to the control of a network of hematopoietic regulators. The expression of c-Kit in erythroid progenitors was tightly dependent on c- Myb levels. Finally, we demonstrated that c-Myb acts as a coordinator at the CFU-E stage by promoting further progression while supporting terminal cell divisions. NFE2L3 nuclear factor Activates erythroid-specific, globin gene Red blood cell (erythroid- expression health derived 2)-like 3 SMAP1 stromal SMAP-1 may have a stimulatory effect Red blood cell membrane- on stroma-supported erythropoiesis. health associated protein 1 ZNF266 zinc finger HZF1 play important roles in erythroid Red blood cell protein 266 and megakaryocytic differentiation. health Increased HZF1 mRNA expression was observed following erythroid differentiation of K562 cells induced by hemin or megakaryocytic differentiation of K562 cells induced by phorbol myristate acetate (PMA). Both of the antisense method and RNA interference assay revealed that RNPS1 \RNA binding Formation of transcription-induced R- RNA Quality protein S1, loops poses a critical threat to genomic Control serine-rich integrity throughout evolution., RNA domain\“” binding protein RNPS1 alleviates ASF/SF2 depletion-induced genomic instability. RNPS1, that when overexpressed strongly suppresses the high molecular weight (HMW) DNA fragmentation, hypermutation, and G2 cell cycle arrest phenotypes of ASF/SF2- depleted cells. Involved in RENT2- dependent nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Also mediates increase of mRNA abundance and translational efficiency. Binds spliced mRNA 20-25 nt upstream of exon-exon junctions, low NMD efficiency is shown to be functionally related to the reduced abundance of the exon junction component RNPS1 PAPOLG poly(A) This gene encodes a member of the RNA Quality polymerase poly(A) polymerase family which Control gamma catalyzes template-independent extension of the 3′ end of a DNA/RNA strand. This enzyme is exclusively localized in the nucleus and exhibits both nonspecific and CPSF (cleavage and polyadenylation specificity factor)/AAUAAA-dependent polyadenylation activity. DCP2 DCP2 Necessary for the degradation of RNA Quality decapping mRNAs, both in normal mRNA tumover Control enzyme and in nonsense-mediated mRNA homolog (S. cerevisiae) decay. DDX5 DEAD (Asp- Nonsense mediated RNA degradation RNA Quality Glu-Ala-Asp) Control box polypeptide 5 ERLIN2 ER lipid raft key ERAD pathway component that may RNA Quality associated 2 act as a substrate recognition factor. Control PARN pol(A)- 3′-exoribonuclease that has a preference RNA quality specific for poly(A) tails of mRNAs, thereby control ribonuclease efficiently degrading poly(A) tails. (deadenylation Exonucleolytic degradation of the nuclease) poly(A) tail is often the first step in the decay of eukaryotic mRNAs and is also used to silence certain maternal mRNAs translationally during oocyte maturation and early embryonic development. Interacts with both the 3′-end poly(A) tail and the 5′-end cap structure during degradation, the interaction with the cap structure being required for an efficient degradation of poly(A) tails. Involved in nonsense-mediated mRNA decay, a critical process of selective degradation of mRNAs that contain premature stop codons. UPF2 UPF2 Nonsense-mediated mRNA decay RNA quality regulator of (NMD) represents a key mechanism to control nonsense control the expression of wild-type and transcripts aberrant mRNAs. Phosphorylation of the homolog protein UPF1 in the context of (yeast) translation termination contributes to committing mRNAs to NMD. UPF3A UPF3 They promote nonsense-mediated RNA quality regulator of mRNA decay (NMD), and they also control nonsense regulate translation efficiency. transcripts homolog A (yeast) TRNT1 \tRNA Adds and repairs the conserved 3′-CCA RNA quality nucleotidyl sequence necessary for the attachment control transferase, of amino acids to the 3′ terminus of CCA-adding, tRNA molecules, using CTP and ATP as 1\“” substrates. MAT2B \methionine Methionine adenosyltransferase (MAT; SAM adenosyltransferase S-adenosyl-L-methionine synthetase, Biosynthetic II, EC 2.5.1.6)1 is an essential enzyme that machinary beta\“” catalyzes the synthesis of S- adenosylmethionine (AdoMet) from L- methionine (L-Met) and ATP (1, 2). AdoMet is the major methyl group donor, participating in the methylation of proteins, DNA, RNA, phospholipids, and other small molecules (reviewed in Refs. 3-5). In addition, AdoMet is the ultimate source of the propylamine moiety used in polyamine biosynthesis, and it serves as co-factor for other key enzymes in the one-carbon metabolism pathway. Methionine adenosyltransferase (MAT; EC 2.5.1.6) catalyzes the biosynthesis of S-adenosylmethionine (AdoMet) from methionine and ATP. MAT II is a broadly expressed MAT consisting of catalytic alpha and noncatalytic beta subunits encoded by MAT2A (601468) and MAT2B, respectively. Methionine adenosyltransferase (MAT) catalyzes the biosynthesis of S- adenosylmethionine (AdoMet), a key molecule in transmethylation reactions and polyamine biosynthesis. The MAT II isozyme consists of a catalytic alpha2 and a regulatory beta subunit. Down- regulation of the MAT II beta subunit expression causes a 6-10-fold increase in intracellular AdoMet levels. SKIV2L2 superkiller mutation in skiv2l2 causes defects in cell Skin Health viralicidic proliferation, suggesting that skiv2l2 activity 2-like plays a role in regulating melanoblast 2 (S. cerevisiae) proliferation during early stages of melanocyte regeneration. Skin ALDH18A1 \aldehyde Defects in this enzyme plays a role in Skin health, Nervous dehydrogenase neurodegeneration, joint laxity, skin system 18 family, hyperelasticity. Role in L-Proline health member A1\“” biosynthesis KIT Mast/stem cell mobilization of hematopoetic stem cells Stem cell growth factor into peripheral blood; marker for HSCs health receptor and MSCs precursor FLT3 FMS-like restricted to CD34+ (high proportion of Stem cell tyrosine stem/progenitor cells) health kinase 3) ITK IL2-inducible play a role in T cell proliferation and Stem cell T-cell kinase differentiation health CD74 Cluster of Hematopoietic Stem Cell survival Stem cell Differentiation pathway health 74 HOXB2 Homeobox Expressed in erythromegakaryocytic Stem cell B2, cells and Hematopoietic Stem Cells health CIAPIN1 Cytokine Necessary for hematopoiesis Stem cell induced health apoptosis inhibitor 1 NOTCH4 hematopoietic stem/progenitor cells Stem cell health NCOR1 nuclear NCOR, a repressor or transcription, is a Stem cell receptor co- principal regulator in neural stem cells health repressor 1 PUM2 pumilio Sequence-specific RNA-binding protein Stem cell homolog 2 that regulates translation and mRNA health (Drosophila) stability by binding the 3′-UTR of mRNA targets. Its interactions and tissue specificity suggest that it may be required to support proliferation and self- renewal of stem cells by regulating the translation of key transcripts. SLAIN2 \SLAIN motif Slain1 was expressed at the stem cell Stem cell family, and epiblast stages of ESC health member 2\“” differentiation ACVR1 \activin A Necessary for proper skeletal/bone Stem cell receptor, type formation; regulate the fate of health I\“” hematopoietic progenitor and stem cells during development PDCD4 programmed The translation inhibitor programmed cell Tumor cell death 4 death 4 (Pdcd4) suppresses suppresor (neoplastic tumorigenesis and invasion. transformation inhibitor) AXIN2 \axin 2 The Axin-related protein, Axin2, Tumor (conductin, presumably plays an important role in suppressor axil)\“” the regulation of the stability of beta- function catenin in the Wnt signaling pathway, like its rodent homologs, mouse conductin/rat axil. In mouse, conductin organizes a multiprotein complex of APC (adenomatous polyposis of the colon), beta-catenin, glycogen synthase kinase 3-beta, and conductin, which leads to the degradation of beta-catenin. Apparently, the deregulation of beta- catenin is an important event in the genesis of a number of malignancies. The AXIN2 gene has been mapped to 17q23-q24, a region that shows frequent loss of heterozygosity in breast cancer, neuroblastoma, and other tumors. Mutations in this gene have been associated with colorectal cancer with defective mismatch repair. AZIN1 antizyme It has been shown to regulate DNA Tumor inhibitor 1 methylation and has tumor suppressor suppressor activity, enhances the nonhomologous function end-joining repair of DNA double-strand breaks in human oral cancer cells. BECN1 \beclin 1 UVRAG interacts with Beclin 1, leading Tumor (coiled-coil, to activation of autophagy and thereof suppressor myosin-like inhibition of tumorigenesis. function BCL2 interacting protein)\“” CREBBP CREB binding CBP has tumor suppressing activity. CBP Tumor protein may function as a ‘master-switch’ suppressor (Rubinstein- between energy storage and function Taybi expenditure, long term memory. syndrome) CREBL2 cAMP potential tumor suppressor Tumor responsive suppressor element function binding protein-like 2 DIDO1 death inducer- Putative transcription factor, weakly pro- Tumor obliterator 1 apoptotic when overexpressed (By suppressor similarity). Tumor suppressor. function ING2 \inhibitor of Tumor suppressor Tumor growth family, suppressor member 2\“” function KRAS v-Ki-ras2 Pfeifer (2001) noted an interesting Tumor Kirsten rat parallel to the p53 (191170) tumor suppressor sarcoma viral suppressor, which was initially described function oncogene as an oncogene, carrying point homolog mutations in tumors. Later it was discovered that it is, in fact, the wildtype copy of the gene that functions as a tumor suppressor gene and is capable of reducing cell proliferation MTSS1 metastasis putative metastasis suppressor gene Tumor suppressor 1 suppressor function RB1 retinoblastoma Key regulator of entry into cell division Tumor 1 (including that acts as a tumor suppressor. Directly suppressor osteosarcoma) involved in heterochromatin formation by function maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. SDCCAG1 serologically can function as a tumor suppressor in Tumor defined colon human lung cancer cells. suppressor cancer function antigen 1 SMAD4 SMAD family Common mediator of signal transduction Tumor member 4 by TGF-beta (transforming growth suppressor factor) superfamily; SMAD4 is the function common SMAD (co-SMAD). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. May act as a tumor suppressor. STK3 \serine/threonine Novel tumor suppressor function. Tumor kinase 3 Stress-activated, pro-apoptotic kinase suppressor (STE20 which, following caspase-cleavage, function homolog, enters the nucleus and induces yeast)\“” chromatin condensation followed by internucleosomal DNA fragmentation. UVRAG UV radiation UVRAG interacts with Beclin 1, leading Tumor resistance to activation of autophagy and thereof suppressor associated inhibition of tumorigenesis. function gene WWOX WW domain critical tumor suppressor gene Tumor containing suppressor oxidoreductase function FOXO1 forkhead box Tumor suppressor and essential role in Tumor Immune O1 the Maintenance of hematopoetic stem suppressor Health cells function TFRC \transferrin receptor (p90, CD71)\“” 

1. A method for modulating the expression of genes related to chromatin stability by administering an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary, the composition modulating the expression of genes related to chromatin stability
 2. The method of claim 1, wherein said administering step includes administering the composition to a subject in the form of three tablets, each tablet administered twice a day.
 3. The method of claim 1, wherein said administering step includes administering a composition that up-regulates the expression of chromatin stability-related genes.
 4. A method of modulating the expression of DNA repair-related genes by administering an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary, the composition modulating the expression of genes related to DNA repair.
 5. The method of claim 4, wherein said administering step including administering the composition to a subject in the form of three tablets, each tablet administered twice a day.
 6. The method of claim 4, wherein said administering step includes administering the composition thereby up-regulating the expression of DNA repair-related genes.
 7. A method for reducing the risk of chromatin damage by administering an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary, the composition modulating the expression of genes thereby reducing the risk of chromatin damage.
 8. The method of claim 7, wherein said administering step including administering the composition to a subject in the form of three tablets, each tablet administered twice a day.
 9. The method of claim 7, wherein said administering step includes administering a composition that up-regulates the expression of chromatin stability-related genes.
 10. A combinatorial therapy comprising: an effective amount of a composition comprising a fruit ingredient, a vegetable ingredient and an herbal ingredient, wherein the fruit, ingredient is at least one of pomegranate and citrus bioflavonoids, wherein the vegetable ingredient is at least one of asparagus, lutein, lycopene and watercress, and wherein the herbal ingredient is at least one of basil, oregano and rosemary, the composition modulating the expression of genes thereby reducing a risk of chromatin damage; and a second composition for treating a disease, wherein said second composition alters chromatin stability.
 11. The combinatorial therapy of claim 10 further comprising alfalfa, brassica, and kale.
 12. The combinatorial therapy of claim 10 further comprising vitamins and minerals.
 13. The combinatorial therapy of claim 12, wherein the vitamins are chosen from vitamin A, vitamin C, vitamin D, vitamin E, niacin, vitamin B₆, vitamin B₁₂, folic acid, biotin, and pantothenic acid.
 14. The combinatorial therapy of claim 12 wherein the minerals are chosen from calcium, magnesium, iodine, potassium, copper, zinc, phosphorus, manganese, chromium, selenium, and molybdenum.
 15. The combinatorial therapy of claim 10 wherein the citrus bioflavonoids are in concentrate form and include naringen, hesperidin and narirutin.
 16. The combinatorial therapy of claim 10 wherein the fruit ingredient, the vegetable ingredient and the herbal ingredient are present in a ratio of 3.5:1:1. 